GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases

Phase 1

Active, not recruiting

• Conditions: Leptomeningeal Metastasis; Brain Metastases
• Interventions: Drug: GDC-0084; Radiation: whole brain radiation therapy radiation

• Registration Number: NCT04192981
• Lead Sponsor: Memorial Sloan Kettering Cancer Center

Brief Summary

This study will test the safety of the study drug, GDC-0084, in combination with radiation therapy in people who have solid tumor brain metastases or leptomeningeal metastases. All participants will have cancer with a PIK3CA mutation. The researchers will test increasing doses of GDC-0084 to find the highest dose that causes few or mild side effects in participants. The study will also try to find out if the combination of the study drug with radiation is effective against participants' cancer.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study Start: 2019-12-06
• Study First Submitted: 2019-12-06
• Study First Submitted QC: 2019-12-06
• Study First Posted: 2019-12-10
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-16
• Last Update Posted: 2024-04-17
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• Histologically confirmed solid tumor malignancies harboring PIK3CA mutations which include mutations in any of the following genes: PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3C2G, PIK3C3, INPP4A, INPP4B, INPPL1, INPP5D, PTEN, AKT1, AKT2, AKT3, and MTOR.

• Brain metastases and/or leptomeningeal metastases involving the brain demonstrated by MR imaging of the brain. For patients with brain metastases, measurable lesion by RANO-BM is required28. Patients with spine leptomeningeal metastases are eligible for the study if they have leptomeningeal metastases of the brain demonstrated by MRI imaging of the brain.

• KPS ≥ 70

• Age ≥ 18 years

• Able to provide informed consent.

• If a patient is on corticosteroid, he/she must be on a stable daily dose of < 4mg dexamethasone or equivalent. Patient does not need to be given corticosteroid as prophylaxis if not clinically indicated.

• No limit to prior therapies with the last systemic therapy ≥ 1 week from initiation of protocol therapy. Systemic therapy can resume after completion of protocol DLT assessment period.

• Patients with prior SRS are eligible, provided that there are new, non-irradiated brain lesions or leptomeningeal metastases. Patients must be ≥ 3 months post prior cranial radiation therapy.

• Patients with seizure history related to brain metastases or leptomeningeal metastases controlled on antiepileptic medications are eligible.

• Patient at reproductive potential must agree to practice an effective contraceptive method

• Patient must be able to swallow and retain oral medication

• Adequate organ function as assessed by laboratory tests.

• Adequate bone marrow function

  • Hemoglobin ≥ 8g/dL
  • Absolute neutrophil count ≥1,000/mm^3
  • Platelet count ≥ 100,000/mm^3

• Adequate liver function

  • Bilirubin ≤1.5 times upper limit normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • Alkaline phosphatase ≤ 2 times ULN

• Adequate renal function ° BUN and Creatinine ≤ 1.5 times ULN

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Exclusion Criteria

• Previous radiotherapy to the intended treatment site that precludes developing a treatment plan that respects tissue tolerances
• Patients with brain metastases eligible for single fraction stereotactic radiation therapy
• Serious medical co-morbidities precluding radiotherapy
• Insulin-treated diabetes; subjects with diabetes or impaired glucose tolerance that is not treated with insulin may be enrolled
• QT interval ≥ 450 msec on EKG
• Cardiac dysfunction defined as: myocardial infarction within 6 months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias
• Known hypersensitivity or intolerance to GDC-0084 or to any other inhibitor of the PI3K/ Akt/ mTOR pathway
• Past medical history of interstitial lung disease, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease
• Subject receiving any medications or substances that are moderate and/or potent enzyme inducers or inhibitors which may have an effect on the metabolism of GDC-0084.
• Pregnant or lactating women.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Concurrent GDC-0084 with Radiation	GDC-0084	GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily, with a potential de-escalation cohort to 30mg, to determine MTD in combination with whole brain radiation therapy radiation therapy to 30Gy in 10 fractions. Once MTD is determined, 12 additional patients will be treated with GDC-0084 at MTD in combination with whole brain radiation therapy.
Concurrent GDC-0084 with Radiation	whole brain radiation therapy radiation	GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily, with a potential de-escalation cohort to 30mg, to determine MTD in combination with whole brain radiation therapy radiation therapy to 30Gy in 10 fractions. Once MTD is determined, 12 additional patients will be treated with GDC-0084 at MTD in combination with whole brain radiation therapy.

Primary Outcome Measures

Name	Time	Method
maximum tolerated dose (MTD)	1 year	Four dose levels will be examined and the maximum tolerated dose (MTD) will be identified.; The standard 3+3 dose-escalation scheme for this study is as follows. Patients will be accrued to the study in cohorts of 3. For any given dose an initial cohort of 3 patients will be treated at that dose.The dose level will be escalated if none of the 3 exhibits any dose limiting toxicity (DLT).

Secondary Outcome Measures

Name	Time	Method
local recurrence rate	1 year	For patients with brain metastases, response determination will be determined using Response Assessment in Neuro-Oncology Brain Metastases criteria28. For patients with leptomeningeal metastases, response assessment will be determined by investigator based on MRI.

Trial Locations

Locations (9)

Memorial Sloan Kettering Basking Ridge (Consent only); 🇺🇸 Basking Ridge, New Jersey, United States

University of Washington (Data Collection AND Data Analysis); 🇺🇸 Seattle, Washington, United States

Memorial Sloan Kettering Cancer Center (All protocol activities); 🇺🇸 New York, New York, United States

BAPTIST ALLIANCE - MCI (Data Collection Only); 🇺🇸 Miami, Florida, United States

Memorial Sloan Kettering Commack (Consent only); 🇺🇸 Commack, New York, United States

Memorial Sloan Kettering Nassau (Consent only); 🇺🇸 Uniondale, New York, United States

Memorial Sloan Kettering Westchester (All protocol activities); 🇺🇸 Harrison, New York, United States

Memorial Sloan Kettering Monmouth (All protocol activities); 🇺🇸 Middletown, New Jersey, United States

Memorial Sloan Kettering Bergen (Consent only); 🇺🇸 Montvale, New Jersey, United States