A Phase 1B Open-Label, Dose-Escalation Study Of The Safety, Tolerability, And Pharmacokinetics Of MEHD7945a And Cobimetinib In Patients With Locally Advanced Or Metastatic Cancers With Mutant KRAS
- Zale Lipshy University Hospital
This is an open-label, multicenter, global Phase ib study designed to assess the safety, tolerability, and pharmacokinetics of intravenous (iV) dosing of MeHD7945a and oral dosing of cobimetinib administered in combination in patients with histologically confirmed, locally advanced, or metastatic solid tumors that carry a KRaS mutation and for which standard therapies do not exist, have proven ineffective or intolerable or are considered inappropriate.
Patient enrollment will be based on the local assessment of KRaS mutation status. Mutational status will be confirmed retrospectively by the Roche Molecular Diagnostics CoBaS KRaS mutation assay based on the required collection of archival tumor tissue samples. Patients whose tumors are not confirmed to exhibit a mutation in KRaS may be replaced.
There are two stages of this study, Stage 1 (dose-escalation) and Stage 2 (indication-specific cohort expansion), which are discussed below. approximately 12[?] 33 patients may participate in the dose-escalation phase, with an estimated 3 [?] 6 patients per cohort. an additional estimated 20 patients may be enrolled in each of two indication-specific expansion cohorts (total number of patients in Stage 2 is approximately 40). Therefore, approximately 52[?] 73 patients may be enrolled in this trial at approximately 8 sites in the united States and Spain.
Patients enrolled in a given cohort will receive MeHD7945a and cobimetinib at a specific dose combination. The initial cohort (Cohort 1) evaluated MeHD7945a administered by iV infusion q2w at its recommended Phase ii dose (RP2D) of 1100 mg in combination with cobimetinib administered once daily (QD) for 21 consecutive days of a 28-day cycle (21/7 dosing schedule) at a dose of 40 mg. MTD was exceeded at this dose and schedule (see Section 1.3.6). The study design has been revised to allow twice weekly dosing of cobimetinib in combination with MeH7945a. For all patients in the study (Stages 1 and 2), the first day of concurrent dosing of MeHD7945a
and cobimetinib is Cycle 1 Day 1.
in the absence of unacceptable toxicity or disease progression, patients deriving clinical benefit may be offered continued treatment with MeHD7945a+ cobimetinib at the discretion of the investigator and provided that study drug is available. administration of MeHD7945a and cobimetinib will be discontinued in patients who experience disease progression or unacceptable toxicity; are not compliant with the study protocol; or, in their opinion or the opinion of the investigator, are not benefiting from study treatment. a study completion/early termination visit will be performed for all patients within 45 days after the last infusion of MeHD7945a or 30 days after last dose of cobimetinib, whichever is later, and patients will be followed for safety until 45 days after the last infusion of MeHD7945a or 30 days after last dose of cobimetinib, whichever is later.
Patients must meet the following criteria for study entry:
* Signed Informed Consent Form (ICF)
* Age>= 18 years
* Locally advanced or metastatic solid KRAS-mutant tumors, for which standard therapies do not exist, have proven ineffective or intolerable or are considered inappropriate
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Life expectancy >= 12 weeks
* Evaluable disease or disease measurable per modified RECIST v1.1
* Adequate hematologic and end organ function, defined by the following laboratory results obtained within 2 weeks prior to first dose of study drug treatment:
x ANC>= 1500/[MICRO-SYMBOL]L
x Platelet count >= 100,000/[MICRO-SYMBOL]L
x Hemoglobin >= 9.0 g/dL
x Albumin >= 2.5 g/dL
x Total bilirubin <=ULN
x AST, ALT, and ALP <= 2.5 x ULN, with the following exceptions:
x Patients with documented liver metastases: AST and/or ALT <= 5 xULN
x Patients with documented liver or bone metastases: ALP <=5 xULN
x Serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of either a 24 hour urine collection or the Cockcroft [?] Gault glomerular filtration rate estimation:
(140 [?] age) x (weight in kilograms) x (0.85 if female) / 72 x (serum creatinine in mg/dL)
x International normalized ratio (INR) and activated partial thromboplastin time (aPTT) <= 1.5 xULN
* For female patients of childbearing potential and male patients with partners of childbearing potential, documented agreement (by patient and/or partner) to use an effective means of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, contraceptive hormone implants) and to continue its use
for the duration of the study and for 45 days for female patients or 135 days for male patients with partners of childbearing potential after the last infusion of study treatment.
* Consent to provide archival tumor tissue for biomarker testing
x A representative FFPE tumor specimen collected at first diagnosis and/or subsequent tumor recurrence(s), i.e., prior to the most recent tumor recurrence, and consistent with the patient[Single Quote]s diagnosis that has adequate viable tumor cells (> 500 non-necrotic tumor cells in a diagnostic slide) either in a tissue block (preferred), or a minimum of 15 (CRC and other tumor types) or 10 (NSCLC) unstained serial slides, is required for participation in this study. This specimen must be reviewed by a pathologist and accompanied by the associated pathology report. The tumor sample and associated pathology report must be confirmed to be available prior to any study specific screening procedures.
x For samples not meeting minimum requirements for size/slide number, contact the Medical Monitor via your site contact with tissue size and tumor content/number of slides to determine eligibility.
x If the archival tumor sample does not meet minimum requirements, the patient may be offered the option of undergoing a pretreatment procedure (excisional or core tumor biopsy) to obtain an adequate tumor sample. A plasma biomarker sample should be collected at the same time as the tumor sample. Additionally, patients who are considered for enrollment into the indication specific expansion cohorts in Stage 2 must meet the following additional eligibility criteria:
* Current cancer must be one of the following:
x KRAS-mutant CRC
x KRAS-mutant NSCLC
* Disease that is measurable per modified RECIST v1.1
* Consent to undergo pretreatment and on-treatment tumor biopsies for pharmacodynamic biomarker analyses (required for patients with KRAS-mutant CRC)
x Optional, but strongly encouraged, for patients with KRAS-mutant NSCLC
* For patients with KRAS-mutant NSCLC: Consent to undergo pretreatment and post-treatment FDG-PET for assessment of pharmacodynamic effect (on-treatment scan only needs to be obtained in patients with FDG-PET avid disease at baseline)