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

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04192981

Collaborator

Kazia Therapeutics (Other)

Enrollment

Locations

Arm

47.8

Anticipated Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Metastases Leptomeningeal Metastasis	Drug: GDC-0084 Radiation: whole brain radiation therapy radiation	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single-arm, prospective trialSingle-arm, prospective trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study With Expansion Cohort of Concurrent GDC-0084 With Radiation Therapy for Patients With Solid Tumor Brain Metastases or Leptomeningeal Metastases Harboring PI3K Pathway Mutations

Actual Study Start Date :

Dec 6, 2019

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Concurrent GDC-0084 with 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.	Drug: GDC-0084 GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily Radiation: whole brain radiation therapy radiation 30Gy in 10 fractions

Arm

Intervention/Treatment

Experimental: Concurrent GDC-0084 with 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.

Drug: GDC-0084

GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily

Radiation: whole brain radiation therapy radiation

30Gy in 10 fractions

Outcome Measures

Primary Outcome Measures

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

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memoral Sloan Kettering Basking Ridge (Consent only)	Basking Ridge	New Jersey	United States	07920
2	Memoral Sloan Kettering Monmouth (All protocol activities)	Middletown	New Jersey	United States	07748
3	Memorial Sloan Kettering Monmouth (All protocol activities)	Middletown	New Jersey	United States	07748
4	Memorial Sloan Kettering Bergen (Consent only)	Montvale	New Jersey	United States	07645
5	Memorial Sloan Kettering Commack (Consent only)	Commack	New York	United States	11725
6	Memoral Sloan Kettering Westchester (All protocol activities)	Harrison	New York	United States	10604
7	Memorial Sloan Kettering Cancer Center (All protocol activities)	New York	New York	United States	10065
8	Memorial Sloan Kettering Nassau (Consent only)	Uniondale	New York	United States	11553