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Study Description

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with acute leukemia. There are 3 arms in Phase 1 as follows: 

• Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/ inducers.
• Arm B: Patients receiving strong cytochrome P450 3A4 (CY3A4) inhibitors for antifungal prophylaxis.
• Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

In Phase 2, patients will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613. There are 3 cohorts in Phase 2 as follows: 

• Cohort 2A: Patients with MLLr acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL).
• Cohort 2B: Patients with MLLr AML.
• Cohort 2C: Patients with NPM1c AML.

Inclusion Criteria

Patients must have active acute leukemia (bone marrow blasts ≥ 5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

• Phase 1: Documented R/R acute leukemia harboring MLL rearrangement or NPM1c mutation.

  • Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers.
  • Arm B: Patients receiving strong cytochrome P450 3A4 inhibitors for antifungal prophylaxis.
  • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

• Phase 2:

  • Cohort 2A: Documented R/R ALL/MPAL with an MLLr translocation.
  • Cohort 2B: Documented R/R AML with an MLLr translocation.
  • Cohort 2C: Documented R/R AML with NPM1c.
• WBC must be below 50,000/ μL at time of enrollment. Patients may receive cytoreduction prior to enrollment.
• Male or female patient aged ≥30 days old.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥40.
• Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
• Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port).
• Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion (DLI) without conditioning.
• Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy.
• Myelosuppressive Chemotherapy: At least 14 days since the completion of cytotoxic/myelosuppressive therapy.
• Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.
• Biologics: At least 7 days or 5 half-lives, whichever is longer, since the completion of therapy with a biologic agent.
• Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.
• Adequate organ function.
• If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.

Exclusion Criteria

• Active diagnosis of acute promyelocytic leukemia.
• Isolated extramedullary relapse.
• Known CNS involvement (cytologic or radiographic).
• Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
• Hepatitis B or C.
• Pregnant or nursing women.
• Cardiac Disease: Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
  • - QTc >450 msec for males and QTc >450 msec for females.

• Gastrointestinal Disease:

  • Chronic diarrhea or other gastrointestinal issue that might affect oral drug absorption or ingestion (ie, short-gut syndrome, gastroparesis, etc).
  • Cirrhosis with a Child-Pugh score of B or C.
• Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
• Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy. Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
• Participation in another therapeutic interventional clinical study within 30 days of enrollment.

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Study Description

This is a single-arm, non-randomized study of re-irradiation of diffuse intrinsic pontine glioma (DIPG)

Study therapy will consist of radiation therapy (RT) given over 17 treatment days (for 30.6 Gy in fractions of 1.8 Gy) or 20 treatment days (for 36 Gy in 1.8 Gy fractions), depending on the time from completion of the first course of RT. Treatment days will generally be weekdays, not including statutory holidays.

Inclusion Criteria

All of these criteria must be met for a patient to be eligible for this study:

1. The patient is 17 years of age or younger at the time of first or second relapse or progression of DIPG
2. The patient has no evidence of metastases on cranial or spinal MR imaging
3. The patient has received RT in the past, given to a total cumulative dose of <60 Gy; prior radiation using opposed lateral fields, conformal 3-D fields, IMRT or using protons is acceptable
4. At least 180 days have elapsed from the last day of primary RT for DIPG
5. The patient has recovered from all acute and subacute toxicities of prior RT and of chemotherapy, if chemotherapy was utilized in the past
6. The patient has been off all anti-tumour therapy for at least 14 days
7. The patient has a Lansky score of 40% or higher
8. The patient has a life expectancy anticipated to be at least 8 weeks with treatment using re-irradiation, with or without dexamethasone
9. The patient has no uncontrolled medical condition (e.g., seizures, diabetes, infection) that would interfere with the delivery of rRT
10. The patient agrees to not enroll on any other clinical trial of an anti-tumour intervention
11. The patient agrees to report and have recorded the use of all medications taken during ReRAD therapy, from the time of diagnosis of progression or recurrence, then through and after completion of, ReRAD therapy; this includes the use of complementary, alternative and dietary therapies
12. The patient is treated at a site where the study is approved by the local ethics board
13. Males and females of child-bearing potential must agree to use effective birth control measures during rRT
14. Consent, and, if applicable, assent, has been obtained according to institutional standards

Exclusion Criteria

If the patient fulfills any of these criteria, then he or she will not be eligible for the study:

1. Females who are pregnant, due to risks from rRT on the developing fetus.
2. Any patient with a condition that prohibits the planned delivery of rRT as prescribed in this study.
3. Patients who are receiving any other clinical trial of an anti-tumour intervention

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Study Description

Brief Summary:

This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric participants with an activating rearranged during transfection (RET) alteration and an advanced solid or primary CNS tumor.

Detailed Description:

This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, participants will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160 milligrams (mg) twice a day (BID). Once the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is identified, participants will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.

With a recent amendment, stable patients who have been on study for over 2 years may discuss the option of a drug treatment holiday with their clinical team. 

Inclusion Criteria

• Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16) performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and effective birth control

Exclusion Criteria

• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant required a modification to current thyroid medication in the 7 days before start of LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s])

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Centres

Study Description

This study will evaluate the safety and efficacy of favezelimab (MK-4280) in combination with pembrolizumab (MK-3475) using a non-randomized study design in participants with the following hematological malignancies:

• classical Hodgkin lymphoma (cHL)
• diffuse large B-cell lymphoma (DLBCL)
• indolent non-Hodgkin lymphoma (iNHL)

This study will also evaluate the safety and efficacy of pembrolizumab or favezelimab administered as monotherapy in participants with cHL using a 1:1 randomized study design.

The study will have 2 phases: a safety lead-in and an efficacy expansion phase. The recommended Phase 2 dose (RP2D) will be determined in the safety lead-in phase by evaluating dose-limiting toxicities.

There is no primary hypothesis for this study.

Inclusion Criteria

• Has measurable disease, defined as ≥1 lesion that can be accurately measured in 2 dimensions with diagnostic quality cross sectional anatomic imaging (computed tomography or magnetic resonance imaging). Minimum measurement must be >15 mm in the longest diameter or >10 mm in the short axis
• Is able to provide a core or excisional tumor biopsy for biomarker analysis from an archival (within 3 months) or newly obtained biopsy at screening
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)

Exclusion Criteria

• Has known clinically active central nervous system (CNS) involvement
• Has received prior therapy with an anti-lymphocyte activation gene-3 (LAG-3) antibody
• Has received chimeric antigen receptors (CAR)-T-cell therapy for cHL and DLBCL Cohorts
• Has received prior anticancer therapy or thoracic radiation therapy within 14 days before the first dose of study treatment
• Has ≥Grade 2 non-hematological residual toxicities from prior therapy
• Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to agents administered ≥4 weeks earlier
• Has received a live vaccine within 30 days prior to first dose of study treatment. Administration of killed vaccines are allowed
• Has received an investigational agent or used an investigational device within 4 weeks prior to intervention administration
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug
• Has a known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring intravenous systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has known, active hepatitis B or hepatitis C infection
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has had an allogeneic hematopoetic stem cell/solid organ transplantation within the last 5 years

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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 

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Study Description

This is an open-label, multicenter study to assess safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy of RO7428731 administered as a monotherapy in participants with newly diagnosed or recurrent epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma (GBM).

Experimental: Part I: Dose Escalation

Participants with newly diagnosed GBM will receive RO7428731, intravenously (IV), up to one year or until disease progression, withdrawal of consent, unacceptable toxicity, or death, whichever occurs first.

Experimental: Part II: Dose-Expansion(s)

Participants with newly diagnosed GBM will receive RO7428731, IV, in maximum of two dose expansion cohorts at a dose(s) not exceeding the maximum tolerated dose (MTD) established in Part I.

Experimental: Part III: Safety Run-in

Participants with recurrent GBM will receive RO7428731, IV in a dosing schedule determined in Part I. At the end of the Safety Run-in period, a decision will be made as to whether to open the Dose-Expansion Cohort Part IVA or open a second Safety Run-in Cohort at a lower dose.

Experimental: Part IV A: Dose-Expansions Cohort

Participants with recurrent GBM will receive RO7428731, IV at specified doses and dosing schedules.

Inclusion Criteria

Inclusion criteria for all participants:

• Life expectancy of greater than or equal to 12 weeks, in the opinion of the Investigator
• Diagnosis of GBM based on World Health Organization (WHO) classification of central nervous system (CNS) tumors, 5th edition
• Participants must have confirmed EGFRvIII-expression
• Karnofsky Performance Status (KPS) Score of >=70%
• Adequate organ functions prior to start of study treatment
• Willingness to abide by contraceptive measures for the duration of the study.

Inclusion criteria for Part I and Part II only:

• Participants whose tumors have an unmethylated (Part I and Part II) or methylated (Part I only) O6-methylguanine-DNA methyltransferase (MGMT) promotor status based on local assessment
• Participants (in Part I): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide. Participants are allowed to have received any number of cycles of temozolomide maintenance. Adult participants with newly diagnosed EGFRvIII-positive GBM with methylated MGMT promotor status who have completed standard of care with surgical resection and adjuvant radiotherapy with concomitant and maintenance temozolomide or discontinued temozolomide maintenance due to reasons other than progressive disease.
• Participants (in Part II): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide.

Inclusion criteria for Part III and Part IV A only:

• Documented first or second recurrence of GBM
• At least one measurable GBM lesion as per Response Assessment in Neuro-Oncology (RANO) criteria prior to initiation of study treatment.

Exclusion Criteria

Exclusion criteria for all participants:

• Participants with infratentorial tumors and tumors primarily located in or close to critical structures (e.g., brain stem)
• Presence of extracranial metastatic or leptomeningeal disease
• Known hypersensitivity to immunoglobulins or to any other component of the investigational medicinal product formulation
• Active bleeding or pathological condition that carries a high risk of bleeding, including inherited and acquired coagulopathies
• Participants unable to undergo an MRI with contrast.

Exclusion criteria for Part I and Part II only:

• Recurrent malignant gliomas
• Any prior anti-tumor treatment for GBM: tumor resection, adjuvant radiotherapy with or without concomitant temozolomide and temozolomide maintenance (Part I only) must be the only tumor-directed treatment that the participant has received for GBM.

Exclusion criteria for Part III and Part IV A only:

• More than two recurrences of GBM
• Prior anti-EGFRvIII-targeting agents (including vaccines), anti-angiogenic therapy, and/or gene therapy for the treatment of GBM and gliomas.

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Study Description

This is a multicenter, open-label, single-arm study to evaluate the safety and dosimetry of Lutathera in adolescent patients 12 to <18 years old with somatostatin receptor positive GEP-NETs and PPGLs. The study will enroll at least 8 patients in the GEP-NET cohort and as many adolescents with PPGL as possible in the exploratory PPGL cohort.

The study schedule for each patient consists of the screening period (up to 2 weeks) followed by the treatment period (4 treatment administrations at 8-week interval), and the follow-up period (5 years).

The treatment period will consist of 4 Lutathera treatments administered at 8-week intervals. Lutathera administration will occur on Week 1 Day 1 of each cycle. Each patient will receive a total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi). An infusion of 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each Lutathera dose for renal protection according to the approved Lutathera local prescribing information. An antiemetic will be administered prior to infusion of the AA solution for prevention of infusion-related nausea and vomiting.

The dosimetry and PK assessments will be performed during the first week after the 1st Lutathera dose, i.e. one time during the study treatment period for each patient. The dosimetry analysis will allow for estimation from the 1st Lutathera administration of the cumulative absorbed radiation dose from 4 Lutathera doses and also for taking a decision on the next dose levels. In the exceptional circumstances when dosimetry cannot be performed in a particular patient after the first Lutathera dose, it should be completed as soon as feasible upon a later dose. In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety data will be performed for each patient in the study, to enable the Investigator to take a decision for the subsequent Lutathera doses. The results of dosimetry assessments (imaging and blood dosimetry) will be provided to the investigators for their evaluation prior to administration of subsequent therapeutic cycles in each patient.

A total follow-up period of 5 years (60 months) after the last Lutathera dose will take place for each patient who received at least one dose of Lutathera. This follow-up period will be comprised of a short-term follow-up of 6 months to evaluate cumulative Lutathera toxicities, followed by a long-term follow up of another 54 months.

Inclusion Criteria

• GEP-NET cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven, G1 or G2 (Ki-67 index =< 20%), well differentiated GEP-NET.

  or PPGL cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven PPGL.

• Patients from 12 to < 18 years of age at the time of enrollment.
• Expression of somatostatin receptors confirmed by a somatostatin receptor imaging (SRI) modality within 3 months prior to enrollment, with tumor uptake Laboratory parameters:observed in the target lesions more or equal to the normal liver uptake.
• Performance status as determined by Karnofsky score >= 50 or Lansky Play-Performance Scale score >= 50.
• Parent's ability to understand and the willingness to sign a written informed consent document for adolescents as determined by local regulations. Adolescents will sign assent along with parental/legal guardian consent or will co-sign consent with parent/legal guardian in accordance with local regulation, prior to participation in the study.

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

Exclusion Criteria

• Laboratory parameters:
  • Estimated creatinine clearance calculated by the Cockroft-Gault method < 70 mL/min
  • Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets <75x109/L.
  • Total bilirubin >3 x ULN for age.
  • Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
• Established or suspected pregnancy.
• Breastfeeding female patients unless they accept to discontinue breastfeeding from the 1st dose until 3 months after the last administration of study drug.
• Female patients of child-bearing potential, unless they are using highly effective methods of contraception during treatment and for 6 months after the last dose of Lutathera.
• Sexually active male patients, unless they agree to remain abstinent or be willing to use effective methods of contraception.
• Patients for whom in the opinion of the investigator other therapeutic options are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.
• Current spontaneous urinary incontinence.
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Hypersensitivity to the study drug active substance or to any of the excipients.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Patients who received any investigational agent within the last 30 days.

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

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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 - Closed to Accrual

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) - Closed to Accrual

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 - Closed to Accrual

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 - Closed to Accrual

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 - Closed to Accrual

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 - Closed to Accrual

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 - Closed to Accrual

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