Clinical trial NCT04192981: GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Brain Metastases
Leptomeningeal Metastasis
Keywords: GDC-0084
Radiation
PIK3CA Mutations
19-359
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: Kazia Therapeutics
First posted: 2019-12-10
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, prospective trial
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: maximum tolerated dose (MTD)
timeFrame: 1 year
Secondary outcomes:
measure: local recurrence rate
timeFrame: 1 year
Other outcomes:
Locations:
city: Miami
country: United States
facility: BAPTIST ALLIANCE - MCI (Data Collection Only)
state: Florida
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge (Consent only)
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth (All protocol activities)
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen (Consent only)
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack (Consent only)
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester (All protocol activities)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (All protocol activities)
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau (Consent only)
state: New York
city: Seattle
country: United States
facility: University of Washington (Data Collection AND Data Analysis)
state: Washington
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Brandon Imber, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: