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Title
Status

 

ONITT - A Randomized Phase I/II Study of Talazoparib or Temozolomide in Combination With Onivyde in Children With Recurrent Solid Malignancies and Ewing Sarcoma

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ONITT - A Randomized Phase I/II Study of Talazoparib or Temozolomide in Combination With Onivyde in Children With Recurrent Solid Malignancies and Ewing Sarcoma

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DiagnosisEwing Sarcoma, Hepatoblastoma, Neuroblastoma, Osteosarcoma, Rhabdoid Tumor, Rhabdomyosarcoma, Wilms, SarcomaStudy StatusOpen
PhaseI/II
AgeChild, Adult - (12 Months to 30 Years) RandomisationYES
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationOnivyde: IV , Talazoparib: oral , Temozolomide: unspecified (oral or IV most likely)
Last Posted Update2023-09-07
ClinicalTrials.gov #NCT04901702
International Sponsor
St. Jude Children's Research Hospital
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
BC Children's Hospital - Dr. Rebecca Deyell
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

Medical contact
Rebecca Deyell

 

Social worker/patient navigator contact
Ilana Katz 

 

Clinical research contact
Hem/Onc/BMT Clinical Trials Unit

 

 

 

Study Description

Brief Summary:

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

 

Detailed Description:

ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumors. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumor patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected.

Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.

Phase I Secondary Objectives

  • To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
  • To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
  • To estimate the antitumor activity of Onivyde plus talazoparib and Onivyde plus temozolomide.

Phase I Exploratory Objectives

  • To describe the relationship between UGT1A1 genotype status with toxicity and response.
  • To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumors.
  • To measure ctDNA at different time points and evaluate its relationship with response to therapy.
  • To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
  • To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase II Primary Objectives

• To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.

Phase II Secondary Objectives

  • To describe the toxicity of the treatment regimens.
  • To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
  • To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.

Phase II Exploratory Objectives

  • To describe the relationship between UGT1A1 genotype status with toxicity and response.
  • To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
  • To describe ctDNA at different time points and the relationship with response to therapy.
  • To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumors who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation.

Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation.

Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumor cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumors (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.

Inclusion Criteria

Patients must be > 12 months and < 30 years at the time of enrollment on study.

Phase I

  • Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment are eligible. Patients must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Patients eligible for the expansion cohort, A2, will include non-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a CLIA-approved (or equivalent) facility.

Phase II

  • Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Refractory disease is defined as progression during first line treatment or within 12 weeks of completion of first line treatment. Recurrent disease includes patients who received first line treatment and experienced disease progression at any time point >12 weeks from the completion of first line therapy.
  • Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated for enrollment.

Disease status

  • Patients must have either measurable or evaluable disease (see Section 7.0 for definitions). Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the OR endpoint.
  • Performance level: Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Prior therapy

Phase I Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible.

Phase II

  • Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse).
  • Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
  • Patients with solid tumors not metastatic to bone marrow:
  • Peripheral absolute neutrophil count (ANC) >1,000/mm3 (1x109/L)
  • Platelet count > 75,000/mm3 (75x109/L) (no transfusion within 7 days of enrollment)
  • Hemoglobin > 9 g/dL (with or without support)

In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as <30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity.

  • Adequate renal function defined as: Creatinine clearance or radioisotope GFR > 60ml/min/1.73m2 or a serum creatinine maximum based on age/sex: age 6months to <1 year, creatinine 0.4; 1 to < 2 years, creatinine 0.6; 2 < 6 years, creatinine 0.8; 6 < 10 years, creatinine 1; 10 to <13 years, creatinine 1.2; 13 to < 16 years creatinine 1.5 (males) or 1.4 (females); > 16 years, creatinine 1.7 (males) 1.4 (females)
  • Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration <5x the institutional ULN, a total bilirubin concentration <2x the institutional ULN for age, and serum albumin > 2g/dL.
  • Adequate pulmonary function defined as no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.
  • Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
  • Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy).
  • Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
  • Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment.
  • Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal RT, 131I-mIBG therapy or substantial bone marrow irradiation (e.g., >50% pelvis irradiation).
  • Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study.
  • Female or male participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment.
Exclusion Criteria

Pregnant or breastfeeding

  • Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose.
  • Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).

LOXO-TRK-15003 (SCOUT) - A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors

Closed to enrollment

LOXO-TRK-15003 (SCOUT) - A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors

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DiagnosisSolid tumors with NTRK fusion, Brain Tumors with NTRK, Fusion infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast cancer Study StatusClosed to enrollment
PhaseI/II
AgeChild, Adult - (up to 21 Years)RandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationOral (capsule or in liquid form)
Last Posted Update2023-09-07
ClinicalTrials.gov #NCT02637687
International Sponsor
Bayer
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
CHU Ste Justine - Dr. Sébastien Perreault
BC Children's Hospital - Dr. Rebecca Deyell
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

Medical contact
Rebecca Deyell

 

Social worker/patient navigator contact
Ilana Katz 

 

Clinical research contact
Hem/Onc/BMT Clinical Trials Unit

 

Medical contact
Dr. Henrique Bittencourt
Dr. Monia Marzouki
Dr. Sebastien Perreault (neuro-onc)
 
Social worker/patient navigator contact
Marie-Claude Charrette
 
Clinical research contact
Marie Saint-Jacques
 

 

 

Study Description

Brief Summary:

The study is being done to test the safety of a cancer drug called larotrectinib in children. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). NTRK gene changes lead to abnormal proteins called TRK fusion proteins, which may cause cancer cells to grow. Larotrectinib blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer.

The first study part (Phase 1) is done to determine what dose level of larotrectinib is safe for children, how the drug is absorbed and changed by their bodies and how well the cancer responds to the drug. The main purpose of the second study part (Phase 2) is to investigate how well and how long different cancer types respond to the treatment with larotrectininb.

Detailed Description:

The primary objectives are to determine the safety and efficacy of oral larotrectinib in pediatric patients with advanced solid or primary central nervous system (CNS) tumors.

The secondary objectives comprise e.g. the determination of the pharmacokinetic properties, the maximum tolerated dose/ recommended dose and the tumor-type specific efficacy of larotrectinib. In addition, pain status and health-related quality of life of the pediatric patients will be assessed.

Inclusion Criteria
  • Phase 1:

    • Dose escalation: Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists; OR Infants from birth and older with a diagnosis of malignancy and with a documented NTRK fusion that has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists; OR Patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase I dose escalation cohorts are closed to enrollment.
    • Dose expansion: In addition to the above stated inclusion criteria, patients must have a malignancy with a documented NTRK gene fusion with the exception of patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer. Patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer may enroll into this cohort with documentation of an ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing.
  • Phase 2:

    • Infants from birth and older at C1D1 with a locally advanced or metastatic infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection; OR Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists with a documented NTRK gene fusion (or in the case of infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing) (identified through molecular assays as routinely performed at CLIA or other similarly certified laboratories). Patients with NTRK-fusion positive benign tumors are also eligible; OR Potential patients older than 21 years of age with a tumor diagnosis with histology typical of a pediatric patient and an NTRK fusion may be considered for enrollment following discussion between the local site Investigator and the Sponsor's Medical Monitor.
  • Patients with primary CNS tumors or cerebral metastasis
  • Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50.
  • Adequate hematologic function
  • Adequate hepatic and renal function
Exclusion Criteria
  • Major surgery within 14 days (2 weeks) prior to C1D1
  • Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1, ongoing cardiomyopathy; current prolonged QTc interval > 480 milliseconds
  • Active uncontrolled systemic bacterial, viral, or fungal infection
  • Current treatment with a strong CYP3A4 inhibitor or inducer. Enzyme-inducing anti-epileptic drugs (EIAEDs) and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
  • Phase 2 only:

    • Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.
Publications

Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Müller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov;30 Suppl 8:viii31-viii35. doi: 10.1093/annonc/mdz382. Epub 2019 Dec 24.

Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24.

Bielack SS, Cox MC, Nathrath M, Apel K, Blattmann C, Holl T, Jenewein R, Klenk U, Klothaki P, Müller-Abt P, Ortega-Lawerenz S, Reynolds M, Scheer M, Simon-Klingenstein K, Stegmaier S, Tupper R, Vokuhl C, von Kalle T. Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii31-viii35. doi: 10.1093/annonc/mdz382.

DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, Anderson ME, Davis JL, Qamoos HE, Reynolds ME, Cruickshank S, Cox MC, Hawkins DS, Mascarenhas L, Pappo AS. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018 Nov 1;124(21):4241-4247. doi: 10.1002/cncr.31701. Epub 2018 Sep 11.

Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, Davis JL, Rudzinski E, Feraco AM, Tuch BB, Ebata KT, Reynolds M, Smith S, Cruickshank S, Cox MC, Pappo AS, Hawkins DS. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018 May;19(5):705-714. doi: 10.1016/S1470-2045(18)30119-0. Epub 2018 Mar 29. Erratum in: Lancet Oncol. 2018 May;19(5):e229.

Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.

BO41932 (TAPISTRY) - Tumor-Agnostic Precision Immunooncology and Somatic Targeting Rational for You (TAPISTRY) Phase II Platform Trial

Open

BO41932 (TAPISTRY) - Tumor-Agnostic Precision Immunooncology and Somatic Targeting Rational for You (TAPISTRY) Phase II Platform Trial

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DiagnosisSolid tumors with eligible genetic changeStudy StatusOpen
PhaseII
AgeChild (Under 18 Years)RandomisationNO
Line of treatmentFirst line treatment, Disease relapse or progression
Routes of Treatment AdministrationEntrectinib - oral Atezolizumab - IV Ipatasertib - oral Alectinib - oral Trastuzumab - IV GDC-0077 (Inavolisib) - oral Belvarafenib - oral Pralsetinib - oral
Last Posted Update2023-08-03
ClinicalTrials.gov #NCT04589845
International Sponsor
Hoffmann-La Roche
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

TAPISTRY is a Phase II, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in rational, specified combinations in participants with unresectable, locally advanced or metastatic solid tumors determined to harbor specific oncogenic genomic alterations or who are tumor mutational burden (TMB)-high as identified by a validated next-generation sequencing (NGS) assay.

Participants with solid tumors will be treated with a drug or drug regimen tailored to their NGS assay results at screening.

Participants will be assigned to the appropriate cohort based on their genetic alteration(s). Treatment will be assigned on the basis of relevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and, unless otherwise specified, will continue until disease progression, loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first.

Cohort A: ROS1 fusion-positive tumors - Open

Participants with metastatic or advanced solid tumors, with the exception of NSCLC will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 milligram per day (mg/day) for pediatric participants with a body surface area (BSA) >/= 1.51 m2

Cohort B: Cohort B: NTRK1/2/3 fusion-positive tumors - Open

Participants with metastatic or advanced solid tumors will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 mg/day for adults and pediatric participants with a BSA >/= 1.51 m2

Cohort C: ALK fusion-positive tumors (excluding NSCLC) - Open

Participants with metastatic or advanced solid tumors, with the exception of NSCLC, will receive alectinib at a dosage of 600 mg orally twice a day (BID), taken with food, in repeated 28-day cycles.

Cohort D: TMB-high tumors - Open

Participants with metastatic or advanced solid tumors will receive atezolizumab intravenously (IV) at a dose of 15 mg/kg (maximum 1200 mg) for participants aged < 18 years on Day 1 of each 21-day cycle.

Cohort E: AKT1/2/3 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive ipatasertib orally once daily (QD). For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants <35 kg, 300 mg for participants >/= 35 and <45 kg, 400 mg for those >/=45 kg orally QD in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent.

Cohort F: HER2 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive trastuzumab emtansine IV at a dose of 3.6 mg/kg every 21 days. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort H: PIK3CA multiple mutant-positive tumors - Open

Participants with metastatic or advanced solid tumors will receive GDC-0077 daily at a starting dose of 9 mg by mouth (PO) in repeated 28-day cycles. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort I: BRAF class II mutant or fusion-positive tumors - Open

Participants with BRAF class II mutant/fusion-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort J: BRAF class III mutant-positive tumors - Open

Participants with BRAF class III mutant-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort K: RET fusion-positive tumors - Open

Participants with RET fusion-positive tumors will self-administer Pralsetinib orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric patients ≥ 12 and < 18 years of age. A treatment cycle consists of 4 weeks (28 days).

Inclusion Criteria
  • In addition to the general inclusion criteria below, participants must meet all of the cohort-specific inclusion criteria for the respective cohort
  • Briefly - for arm A, a ROS1 fusion is required; for arm B, a NTRK1/2/3 fusion is required; for arm D, a TMB >16mut/Mb is required; for arm E: specific mutations in the AKT gene are required; for arm F: specific mutations in the HER2 gene are required; for arm H, specific mutations in the PIK3CA gene are required; for arm I, a BRAF Class II mutation or fusion is required; for arm J, a BRAF Class III mutation is required; for Cohort K; a RET fusion is required. 
  • Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
  • Performance status as follows: Participants aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
  • For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
  • Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
  • Adequate recovery from most recent systemic or local treatment for cancer
  • Life expectancy >= 8 weeks
  • Ability to comply with the study protocol, in the investigator's judgment
  • For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
  • For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
Exclusion Criteria
  • Current participation or enrollment in another therapeutic clinical trial
  • Any anticancer treatment within 2 weeks or 5 half-lives prior to start of study treatment
  • Whole brain radiotherapy within 14 days prior to start of study treatment
  • Stereotactic radiosurgery within 7 days prior to start of study treatment
  • Pregnant or breastfeeding, or intending to become pregnant during the study
  • History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study or confounds the ability to interpret data from the study
  • Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina
  • History of another active cancer within 5 years prior to screening that may interfere with the determination of safety or efficacy of study treatment with respect to the qualifying solid tumor malignancy
  • In addition to the general exclusion criteria above, in order to be enrolled in a treatment cohort of the study, participants must not meet any of the cohort-specific exclusion criteria

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team

JZP712-101 - A Phase 1/2, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Recommended Phase 2 Dose (RP2D), and Efficacy of Lurbinectedin Monotherapy in Pediatric Participants With Previously Treated Solid Tumors Followed by Expansion to Assess Efficacy and Safety in Pediatric and Young Adult Participants With Relapsed/Refractory Ewing Sarcoma.

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JZP712-101 - A Phase 1/2, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Recommended Phase 2 Dose (RP2D), and Efficacy of Lurbinectedin Monotherapy in Pediatric Participants With Previously Treated Solid Tumors Followed by Expansion to Assess Efficacy and Safety in Pediatric and Young Adult Participants With Relapsed/Refractory Ewing Sarcoma.

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DiagnosisRelapsed/Refractory Ewing SarcomaStudy StatusOpen
PhaseI/II
Age2 Years to 30 YearsRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: Lurbinectedin Administered as intravenous (IV) infusion once every 3 weeks (Q3W)
Last Posted Update2023-08-01
ClinicalTrials.gov #NCT05734066
International Sponsor
Jazz Pharmaceuticals
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

This study is conducted in two phases. The phase 1 portion of the study evaluates the safety, tolerability, pharmacokinetics (PK), recommended phase 2 dose (RP2D), and effectiveness of lurbinectedin monotherapy in pediatric participants with previously treated solid tumors. This is followed by the phase 2 portion, to further assess the effectiveness and safety in pediatric and young adult participants with recurrent/refractory Ewing sarcoma.

Inclusion Criteria
  • Participant must meet the following age requirements at the time the informed consent form (ICF) (and assent form, if applicable) is signed:
    • Phase 1 Part 1: participants must be ≥ 2 to < 18 years of age.
    • Phase 1 Part 2: participants must be ≥ 2 to ≤ 30 years of age.
    • Phase 2: participants must be ≥ 2 to ≤ 30 years of age.
  • Participant has a confirmed solid tumor
  • The participant has a Lansky/Karnofsky performance status score of ≥ 50%.
  • The participant has adequate liver function, evidenced by the following laboratory values:
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN).
    • Total bilirubin ≤ 1.5 × institutional ULN (with the exception of participants with Gilbert's syndrome who must have bilirubin < 3 × institutional ULN).
  • The participant has adequate bone marrow function, evidenced by the following:
    • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L (independent of growth factor support within 1 week of screening laboratories).
  • Platelets ≥ 100 × 109/L (without platelet transfusion within previous 7 days of screening laboratories).
    • Hemoglobin ≥ 8 g/dL (note: may have been transfused).
  • The participant has an adequate renal function:
    • Calculated creatinine clearance (use Cockcroft-Gault formula for participants ≥ 18 years; Schwartz equation for participants < 18 years) ≥ 60 mL/min.
  • The participant has an adequate cardiac function:
    • Left ventricular ejection fraction or shortening fraction per institutional norm ≥ institutional lower level of normal.
  • The participant has creatine phosphokinase ≤ 2.5 × institutional ULN.
  • The participant has body weight ≥ 15 kg.
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Male participants 

  • Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 4 months after the last dose of study intervention:
    • Refrain from donating sperm AND
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent 
    • OR must agree to use contraception/barrier as detailed below:
      • Agree to use a male condom with female partner and use of an additional highly effective contraceptive method with a failure rate of < 1% per year when having sexual intercourse with a Woman of childbearing potential (WOCBP) who is not currently pregnant.
      • Note: male participants who are azoospermic (vasectomized or due to a medical cause) are still required to follow the protocol-specified contraception/barrier criteria.

Female participants

  • A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
    • Is a Woman of nonchildbearing potential (WONCBP). OR
    • Is a WOCBP and using an acceptable contraceptive method during the study intervention period (at least 6 months after the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 7 days before the first dose of study intervention
      • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • Additional requirements for pregnancy testing during and after study intervention.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Exclusion Criteria
  • Corrected QT interval (QTc) prolongation defined as a QTc ≥ 470 ms using the Bazett formula.
  • Known symptomatic Central nervous system (CNS) metastases requiring steroids. Participants with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued high dose steroid treatment for these metastases for at least 2 weeks, and are neurologically stable (physiologic doses of steroids and short courses of steroids for other indications are acceptable).
  • Persisting toxicity related to prior therapy; however, alopecia, sensory neuropathy, hypothyroidism, and rash Grade ≤ 2 are acceptable, and other Grade ≤ 2 adverse events (AEs) not constituting a safety risk based on the investigator's judgement are acceptable.
  • An uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy, symptomatic heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Any other major illness that, in the investigator's judgment, could substantially increase the risk associated with participation in this study.
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high-risk for treatment complications.
  • Received prior treatment with lurbinectedin or trabectedin.
  • Received prior treatment with any investigational product within 4 weeks of first infusion of study intervention. Observational studies are permitted.
  • Received live or live attenuated vaccines within 4 weeks of the first dose of study treatment or plans to receive live vaccines during study participation. Administration of inactive vaccines or messenger ribonucleic acid (mRNA) vaccines (for example, inactivated influenza vaccines or COVID-19 vaccines) are allowed.
  • Had major surgery ≤ 4 weeks or radiation therapy ≤ 2 weeks prior to enrollment unless fully recovered. Prior palliative radiotherapy is permitted, provided it was completed at least 2 weeks prior to participant enrollment.
  • Received prior allogeneic bone marrow transplantation or solid organ transplant.
  • Received chemotherapy ≤ 3 weeks prior to start of study intervention.
  • Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or Polymerase chain reaction (PCR) test for HCV RNA if HCV antibody test is positive).
  • Human immunodeficiency infection at screening (positive anti-HIV antibody).
  • Has a known or suspected hypersensitivity to any of the components of the study intervention.
  • The participant or parent(s)/guardian(s) is/are unable to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator

Other exclusion criteria may apply

PBTC-049 - A Phase I Study of Savolitinib in Recurrent, Progressive or Refractory Medulloblastoma, High-Grade Glioma, Diffuse Intrinsic Pontine Glioma, and CNS Tumors Harboring MET Aberrations

Open

PBTC-049 - A Phase I Study of Savolitinib in Recurrent, Progressive or Refractory Medulloblastoma, High-Grade Glioma, Diffuse Intrinsic Pontine Glioma, and CNS Tumors Harboring MET Aberrations

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DiagnosisRecurrent or Refractory Diffuse Intrinsic Pontine Glioma (DIPG), Recurrent or Refractory Malignant Glioma, Recurrent or Refractory Medulloblastoma, Recurrent or Refractory Primary Central Nervous System NeoplasmStudy StatusOpen
PhaseI
Age6 Years to 21 YearsRandomisationN/A
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: Savolitinib (Oral) Other Names: AZD 6094 AZD6094 HMPL-504 Volitinib
Last Posted Update2023-07-27
ClinicalTrials.gov #NCT03598244
International Sponsor
National Cancer Institute (NCI)
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Vijay Ramaswamy
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

 

This phase I trial studies the side effects and best dose of volitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib (savolitinib) administered orally daily in children with refractory, progressive or recurrent primary CNS tumors.

II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study.

II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival [PFS]) and the presence of specific genomic alterations (e.g. MET amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific subgroups of disease.

OUTLINE: This is a dose-escalation study.

Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.

Inclusion Criteria
  • Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
    • Note: Refractory disease is defined as the presence of persistent abnormality on conventional magnetic resonance imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
  • Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. MET pathway activation status must be confirmed using Food and Drug Administration (FDA) approved testing prior to enrollment. MET pathway activation is defined as:
    • MET kinase domain mutations, allelic frequency >= 5% OR
    • MET or HGF amplification, >= 6 copies OR
    • Chromosome 7 gain OR
    • MET fusion
      • If a MET aberration is identified using local testing at a Pediatric Brain Tumor Consortium (PBTC) institution, final confirmation for eligibility to the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study chair review
  • Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
    • Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
  • Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
  • Patients must be > 5 years and =< 21 years of age at the time of study enrollment
  • Body surface area (BSA)
    • Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
    • Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
    • Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67 m^2
    • Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2 and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the dose finding phase only)
  • Patients must have failed prior standard therapy for their tumor. Patients with medulloblastoma must have received radiation therapy in addition to platinum and alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have at least received radiation therapy. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
  • Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if it included nitrosourea
  • Biologic or investigational agent (anti-neoplastic):
    • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
      • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
    • Monoclonal antibody treatment and agents with known prolonged half-lives:
      • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
  • Patients must have had their last fraction of:
    • Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment
    • Focal irradiation > 4 weeks prior to enrollment
  • Patients must be:
    • >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
    • >= 3 months since autologous stem cell transplant prior to enrollment
  • Both males and females of all races and ethnic groups are eligible for this study
  • Neurologic Status
    • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
    • Patients with seizure disorders may be enrolled if seizures are well controlled
    • Patients must be able to swallow whole tablets to be eligible for study enrollment
  • Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
    • Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Absolute neutrophil count >= 1.0 x 10^9 cells/ L
  • Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
  • Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell transfusions are not allowed within 14 days prior to enrollment)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5 x ULN with ALT and AST =< 1 x ULN
  • Albumin >= 2 g/dL
  • Serum creatinine based on age/gender. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
    • Age: Maximum serum creatinine (mg/dL)
    • 2 to < 6 years: 0.8 (male and female)
    • 6 to < 10 years: 1 (male and female)
    • 10 to < 13 years: 1.2 (male and female)
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • >= 16 years: 1.7 (male), 1.4 (female)
  • International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
  • Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for >= 2 weeks
  • Cardiac function:
    • Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3 electrocardiograms (EKGs)
  • Oxygen saturation as measured by pulse oximetry is > 93% on room air
  • Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment
  • Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
  • Pregnancy Prevention
    • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
    • Women of child-bearing potential should use effective contraception from the time of enrollment until 4 weeks after discontinuing study treatment
    • Male study participants should use a condom with female partners of child-bearing potential during the study and for 4 weeks after discontinuing study treatment
    • If the female partner of a male study participant is not using effective contraception, men must use a condom during the study and for 6 months after discontinuing study treatment
    • Male study participants should avoid fathering a child and refrain from sperm donation from study start to 6 months after discontinuing study treatment
  • The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Other inclusion criteria may apply and will be discussed with you by the study team.

Exclusion Criteria
  • Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
  • Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis
  • Patients with any clinically significant unrelated systemic illness or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
  • Patients with uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile for age, height, and gender, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
    • The normal blood pressure by height, age and gender tables can be assessed in the Generic Forms section of the PBTC member's webpage
  • Patients with any of the following cardiac diseases
    • Congestive heart failure (New York Heart Association >= grade 2)
    • Clinically significant cardiac arrhythmia
    • Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
    • Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
    • Family history of unexplained sudden death under 40 years of age in first-degree relatives or
    • Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
  • Concurrent Therapy
    • Patients who are receiving any other anticancer or investigational drug therapy
    • Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates should not be used during the trial or used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. Patient drug information handout and wallet card should be provided to patients
    • Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib, cabozantinib, or onartuzumab)
  • Patient is currently receiving any of the following herbal preparations or medications and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's wort). These herbal medications include, but are not limited to: cannabis products, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
  • Patient has undergone major surgical procedure =< 28 days prior to beginning study drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting is required following port-a-cath placement
  • Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
  • Prisoners will be excluded from this study

Other exclusion criteria may apply and will be discussed with you by the study team.

23ME-00610-CLIN-001 - A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion Study of Intravenously Administered 23ME-00610 in Patients With Advanced Solid Malignancies

Open

23ME-00610-CLIN-001 - A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion Study of Intravenously Administered 23ME-00610 in Patients With Advanced Solid Malignancies

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DiagnosisSolid TumorStudy StatusOpen
PhaseI
Age12 Years and olderRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: 23ME-00610 (IV infusion)
Last Posted Update2023-06-29
ClinicalTrials.gov #NCT05199272
International Sponsor
23andMe, Inc.
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

This study includes a dose-escalation phase in Part A to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) followed by 5 monotherapy expansion arms in Part B to further evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of 23ME-00610 in patients with solid malignancies. Only Part B is open at pediatric sites. 

Primary Outcome Measures:

  1. Part A: Incidence and severity of dose-limiting toxicities (DLTs) 
  2. Part B adolescents: Incidence and severity of dose-limiting toxicities (DLTs) 
  3. Part A: Incidence and severity of adverse events (AEs) 
  4. Part B adolescents: Incidence and severity of adverse events (AEs)
  5. Part A: Incidence and severity of serious adverse events (SAEs) 
  6. Part B adolescents: Incidence and severity of serious adverse events (SAEs) 
  7. Part A: Incidence of withdrawals due to AEs
  8. Part B adolescents: Incidence of withdrawals due to AEs 
  9. Part B: Objective response rate (ORR) 

    ORR based on investigator assessment against RECIST 1.1 criteria

Secondary Outcome Measures:

  1. Prevalence and incidence of antidrug antibodies (ADA) to 23ME-00610 [ Time Frame: Up to 5 days post treatment discontinuation ]
  2. Part A: Objective response rate (ORR) [ Time Frame: From baseline until disease progression (up to 5 years) ]

    ORR based on investigator assessment against RECIST 1.1 criteria

  3. Duration of response (DoR) [ Time Frame: Up to 5 years ]

    Duration of response based on investigator assessment against RECIST 1:1 criteria

  4. Disease Control Rate (DCR) [ Time Frame: Up to 5 years ]

    Disease control rate based on investigator assessment against RECIST 1:1 criteria

  5. Progression free survival (PFS) [ Time Frame: Up to 5 years ]

    Progression free survival based on investigator assessment against RECIST 1:1 criteria

  6. Overall survival (OS) [ Time Frame: Up to 5 years ]
  7. Maximum serum concentration (Cmax) following a single dose of 23ME-00610 
  8. Time of maximum serum concentration (Tmax) following a single dose of 23ME-00610 
  9. Area under the concentration-time curve from zero to the last measurable concentration (AUClast) following a single dose of 23ME-00610 
  10. Last measurable serum concentration (Clast) following a single dose of 23ME-00610
  11. Area under the concentration-time curve from zero extrapolated to infinity (AUCinf) following a single dose of 23ME-00610 
  12. Terminal half-life (T1/2) following a single dose of 23ME-00610
  13. Maximum serum concentration (Cmax) following multiple doses of 23ME-00610
  14. Time of maximum serum concentration (Tmax) following multiple doses of 23ME-00610
  15. Area under the concentration-time curve from time zero to the end of the dosing interval (AUCtau) following multiple doses of 23ME-00610
  16. Serum concentration at the end of the dosing interval (Ctau) following multiple doses of 23ME-00610
  17. Terminal half-life (T1/2) following multiple doses of 23ME-00610
Inclusion Criteria
  • Part A: Adults ≥ 18 years of age; Part B: ≥ 12 to years of age, weighing at least 40 kg (total body weight)
  • Histologically-diagnosed locally advanced (unresectable), or metastatic solid cancer that has progressed after all available standard therapy for the specific tumor type, or for which all available standard therapy has proven to be ineffective or if no further standard therapy exists.
  • Part A: Adults 18+: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; Part B: Adolescents ≥ 12 to < 16 years of age: Lansky Play Scale ≥ 50; Adolescents ≥ 16 years of age: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
  • Life expectancy ≥ 12 weeks
  • Part A: Patients without RECIST measurable disease (e.g., evaluable disease only) will be eligible for enrollment in Part A, regardless of tumor type; Part B: Patients enrolled in Part B must have measurable disease by per RECIST 1.1 and have ≥ 1 site of measurable disease that has not been previously irradiated.

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team 

Exclusion Criteria
  1. Females who are pregnant (positive serum pregnancy test within 7 days prior to study drug administration) or breastfeeding.
  2. Immune Related Medical History:
    • Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years
    • Receipt of systemic immunosuppressive therapy (e.g. steroids) within 4 weeks prior to the start of study drug administration
    • History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, non-infectious pneumonia that required steroids, or evidence of active, non-infectious pneumonitis
    • History of Grade ≥ 3 immune-mediated toxicity
  3. Prior allogeneic or autologous bone marrow transplant, or other solid organ transplant.
  4. History of a positive test for:
    • Hepatitis C virus (HCV) infection, except for those who have completed curative therapy for HCV and have undetectable HCV RNA
    • Hepatitis B virus (HBV) infection, except for those who are receiving treatment with HBV-active nucleos(t)ide antiviral therapy at the time of study entry and have undetectable HBV DNA
    • Human Immunodeficiency Virus (HIV) infection, except those who meet the following criteria: CD4+ T cells ≥ 350 cells/μL, no history of Acquired Immunodeficiency Syndrome (AIDS)-defining opportunistic infections, HIV RNA < 50 copies/mL, and on a stable antiretroviral regimen for at least 3 months.
  5. Prior radiation therapy with an inadequate washout between the last dose and the start of study drug, defined as follows: 1) at least 2 weeks for palliative radiation to the extremities for osseous bone metastases is required; 2) at least 4 weeks for radiation to the chest, brain, or visceral organs is required; and 3) at least 6 weeks for large-field radiation is required.
  6. Prior anticancer therapy, including chemotherapy, targeted therapy, biological therapy or immune-checkpoint inhibitors within 4 weeks or 5 drug half-lives (whichever is shorter)
  7. History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease free.
  8. Recent history of cardiovascular disease
  9. Uncontrolled or symptomatic CNS (central nervous system) metastases and/or carcinomatous meningitis

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team 

DAY101-102 - A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination With Other Therapies for Patients With Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations

Open

DAY101-102 - A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination With Other Therapies for Patients With Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations

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DiagnosisNon-hematological tumours (solid and brain) with relevant biomarkerStudy StatusOpen
PhaseI/II
Age12 Years and olderRandomisationNO
Line of treatmentDisease relapse or progression
Routes of Treatment AdministrationDrug: DAY101 (Oral tablet) Drug: Pimasertib Hydrochloride (Oral capsule) - Sub-study B only.
Last Posted Update2023-06-27
ClinicalTrials.gov #NCT04985604
International Sponsor
Day One Biopharmaceuticals, Inc.
Principal Investigators for Canadian Sites
The Hospital for Sick Children - Dr. Daniel Morgenstern
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent or progressive solid (including CNS) tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway. Study DAY101-102 (master study) and sub-studies will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period where survival, status and subsequent anticancer therapies are collected.

DAY101 will be evaluated alone (sub-study A) or combined with a different targeted therapy (sub-study B) in each sub-study. The Phase 1b part of each sub-study will evaluate the safety of the combination and select the dose for the Phase 2 part. The Phase 2 part of each sub-study will evaluate anti-tumor activity.

Inclusion Criteria
  • Signed assent for patients ≥ 12 up to < 18 years of age
  • Patients must have a histologically confirmed diagnosis of non-hematological tumor with concurrent MAPK pathway alteration as assessed by sequencing, PCR, FISH, or another clinically accepted molecular diagnostic method recognized by local laboratory or regulatory agency
  • Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1)
  • Archival tumor tissue (preferably less than 3 years old) or fresh tumor tissue for correlative studies is required
  • If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging

Other inclusion criteria may apply

Exclusion Criteria
  • Known presence of concurrent activating mutation
  • Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

Substudy A-specific exclusion criterion:

  • Prior therapy of any RAS- RAF-, MEK-, or ERK-directed inhibitor therapy

Substudy B-specific exclusion criterion:

  • Prior receipt of any Type-II pan-RAF inhibitor therapy (e.g., LXH254/naporafenib, BGB- 283, BGB-3245, belvarafenib)

Other exclusion criteria may apply 

BT016C - HIFU - A Safety and Feasibility Study to Evaluate Blood Brain Barrier Disruption Using Exablate MR Guided Focused Ultrasound in Combination With Doxorubicin in Treating Pediatric Patients With Diffuse Intrinsic Pontine Gliomas (DIPG)

Open

BT016C - HIFU - A Safety and Feasibility Study to Evaluate Blood Brain Barrier Disruption Using Exablate MR Guided Focused Ultrasound in Combination With Doxorubicin in Treating Pediatric Patients With Diffuse Intrinsic Pontine Gliomas (DIPG)

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DiagnosisBrain TumorStudy StatusOpen
PhaseI/II
Age5 Years to 18 YearsRandomisationNO
Line of treatmentFirst line treatment
Routes of Treatment AdministrationDevice: Exablate Model 4000 Type 2.0/2.1 Drug: Doxorubicin
Last Posted Update2023-06-26
ClinicalTrials.gov #NCT05615623
International Sponsor
InSightec
Principal Investigators for Canadian Sites
The Hospital for Sick Children (SickKids) - Dr. James Rutka
Centres
Medical contact

Dr. Daniel Morgenstern

daniel.morgenstern@sickkids.ca

Social worker/patient navigator contact

Karen Fung 

karen.fung@sickkids.ca

Clinical research contact

NAIT Program 

nait.info@sickkids.ca

 

 

 

Study Description

This is a prospective, single arm, non-randomized feasibility study to evaluate the safety, feasibility and preliminary efficacy of Blood Brain Barrier Disruption (BBBD) using the Exablate Type 2 system in pediatric patients with Diffuse Intrinsic Pontine Gliomas (DIPG) undergoing Doxorubicin chemotherapy. The study will be conducted at a single center in Canada. Patients will undergo 3 treatment cycles, approximately 4 -6 weeks apart. The study aims to establish feasibility and safety of Exablate BBBD in conjunction with Doxorubicin in the treatment of pediatric DIPG and assess preliminary efficacy in this patient population.

Inclusion Criteria
  • Age between 5 and 18 years, inclusive
  • Patient diagnosed with DIPG
  • At least 4-week and not greater than 12 weeks from completion of radiation therapy
  • Post-radiation imaging does not show evidence of necrosis/ hemorrhage or other features that contraindicate MRgFUS
  • Able to attend all study visits and with life expectancy of at least 6 months
  • Able and willing to give consent and/or assent or have a legal guardian who is able and willing to do so
  • If on steroids, stable or decreasing dose for at least 7 days prior to study entry
  • If brain surgery occurred, at least 14 days passed since last brain surgery and the patient is fully recovered and neurologically stable
Exclusion Criteria
  • Evidence of cranial or systemic infection
  • Known life-threatening systemic disease
  • Previous treatment with complete cumulative doses of Doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones
  • Contraindication to Doxorubicin. - Known sensitivity to DEFINITY® ultrasound contrast agent or known hypersensitivity to perflutren microsphere or its components, e.g., polyethylene glycol. - Known sensitivity to gadolinium-based contrast agents
  • Active seizure disorder or epilepsy (seizures despite medical treatment) for a minimum of 4 weeks prior to first cycle/Exablate BBBD procedure captured by history
  • Patients with positive HIV status. - Immunosuppression (corticosteroids to prevent/treat brain edema are permitted)
  • Cerebral or systemic vasculopathy, including intracranial thrombosis, vascular malformation, cerebral aneurysm, or vasculitis
  • Hypertension per age
  • History of a bleeding disorder, coagulopathy or with a history of spontaneous tumour hemorrhage
  • Anti-coagulant therapy, or medications known to increase risk of hemorrhage, (e.g., ASA, non-steroidal anti-inflammatory drugs [NSAIDs], statins) within washout period prior to treatment
  • Patient receiving bevacizumab (Avastin) therapy or increasing doses of steroids
  • Symptoms and signs of increased intracranial pressure
  • Previous participation in other chemotherapy, molecularly targeted therapy or immunotherapy treatment-related phase 1 or 2 trials
  • Tumor not visible on any pre-therapy or post-radiation imaging