AMG 510 in Combination with Carboplatin and Pemetrexed or with Docetaxel in Subjects with NSCLC with KRAS p.G12C Mutation (Amgen Subprotocol F)
A Phase 1b Study Evaluating the Safety, Tolerability, and Efficacy of AMG 510 in Combination with Carboplatin and Pemetrexed or with Docetaxel in Subjects with Advanced Non-small Cell Lung Cancer (NSCLC) with KRAS p.G12C Mutation
To evaluate the safety and tolerability of sotorasib administered in investigational regimens in adult subjects with KRAS p.G12C mutant advanced solid tumors.
Key Inclusion Criteria
For a patient to be eligible for participation in this study, all of the following criteria must apply.
- Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
- Age ≥ 18 years
- Pathologically documented, locally-advanced or metastatic NSCLC with KRAS p.G12C mutation identified through molecular testing. KRAS p.G12C mutation must be identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC or be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
- Subjects must have received:
- For Part 1 (dose exploration) of either Cohort A or B:
- Anti-PD1 or anti-programmed death-ligand 1 (PD-L1) immunotherapy (unless contraindicated) AND/OR prior platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified (ie, EGFR, ALK, and ROS1).
- Subjects who have refused standard therapy.
- For Part 2 (dose expansion) of Cohort A:
- Anti-PD1 therapy alone (not with platinum-based combination chemotherapy) unless contraindicated.
- Subjects who have previously achieved at least stable disease on a platinum-based combination chemotherapy that was completed more than 6 months
- Subjects who have progressed more than 6 months after completion of prior neoadjuvant/adjuvant chemotherapy. Subjects who have refused standard therapy.
- For Part 2 (dose expansion) of Cohort B:
- Anti-PD1 or anti- PD-L1 immunotherapy AND/OR prior platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified (ie, EGFR, ALK, and ROS1).
- Subjects who have progressed on or within 6 months of completion of prior
- For Part 1 (dose exploration) of either Cohort A or B:
- Measurable disease per RECIST 1.1 criteria
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
- Life expectancy of > 3 months, in the opinion of the investigator
- Ability to take oral medications and willing to record daily adherence to investigational product
- Corrected QT interval (QTc) ≤ 470 msec for women and ≤ 450 msec for men (based on average of screening triplicates
- Adequate hematological laboratory assessments, as follows:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL
- Adequate renal laboratory assessments, as follows:
• Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥ 60 ml/min/1.73 m2
- Adequate hepatic laboratory assessments, as follows:
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal (ULN), except if alkaline phosphatase > 2.5 times the ULN, then AST and/or ALT must be ≤ 1.5 times the ULN
- Total bilirubin ≤ ULN
- Adequate coagulation laboratory assessments, as follows:
• Partial prothrombin time (PTT) or partial thromboplastin time (PTT) < 1.5 x ULN, OR international normalized ratio (INR) < 1.5 x ULN or within target range if on prophylactic anticoagulation therapy
Key Exclusion Criteria
A patient will not be eligible for participation in this study if any of the following criteria apply.
- Mixed small-cell lung cancer and NSCLC histology
- Active brain metastases and/or carcinomatous meningitis from non-brain tumors. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade ≤ 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 30 days shows no new lesions appearing
- Leptomeningeal disease.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly. Patients with PleurX catheters in place may be considered for the study with Medical Monitor approval.
- History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years
- History of other malignancy within the past 2 years, with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Adequately treated breast ductal carcinoma in situ without evidence of disease.
- Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- Adequately treated urothelial papillary noninvasive carcinoma or carcinoma
- Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication
- Gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory GI disease (eg, Crohn’s disease, ulcerative colitis)
- Evidence of hepatitis infection based on the following results and/or
• Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute Hepatitis B)
• Negative HepBsAg with a positive for Hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then Hepatitis B surface antibody [anti-HBs] testing is necessary. Undetectable, anti-HBs in this setting would suggest unclear and possible infection, and needs exclusion)
• Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic Hepatitis C.
- Known positive test for human immunodeficiency virus (HIV).
- Is unwilling to take corticosteroid premedication for pemetrexed or docetaxel.
- Is unable or unwilling to take folic acid or vitamin B12 supplementation.
- Has an active infection requiring systemic therapy.
- Prior therapy with AMG 510
- Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy, or investigational agent) within 28 days of study day 1
- Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
- Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment
- Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrow therapeutic window) or Pgp substrates, within 14 days or 5 halflives of the study drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor
- Use of strong inducers of CYP3A4 (including herbal supplements such as St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor.
- Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with
the exception of alopecia (grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible [defined as having been present and stable for > 6 months], such as ifosfamide, related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor).
- Subject unable to receive both iodinated contrasts for CT scans and gadolinium contrast for MRI scans
- Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guérin (BCG), and typhoid vaccine. Season influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg FluMist®) are live attenuated vaccines and are not allowed.