MC# 19-37 - Subprotocol H: A Phase 1b Study Evaluating the Safety, Tolerability, and Efficacy of AMG 510 in Combination with Panitumumab and in Combination with Panitumumab and FOLFIRI in Subjects with Advanced Solid Tumors with KRAS p.G12C Mutation

  • Agent(s): AMG 510, EFGR Inhibitor, Chemotherapeutic regimen
  • Disease Type(s): Colorectal, Pancreatic, Solid Tumor, Lung-NSCLC
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): KRAS G12C

Mechanism of Action

An orally available agent that targets the specific KRAS mutation, p.G12C, with potential antineoplastic activity.  Upon oral administration, sotorasib selectively targets the KRAS p.G12C mutant, at either the DNA, RNA or protein level, and prevents, through an as of yet not elucidated manner, expression of and/or tumor cell signaling through the KRAS p.G12C mutant.  This may inhibit growth in KRAS p.G12C-expressing tumor cells.  The KRAS p.G12C mutation is seen in some tumor cell types and plays a key role in tumor cell proliferation.

Purpose

To evaluate the safety and tolerability of sotorasib administered in investigational regimens in adult subjects with KRAS p.G12C mutant advanced solid tumors.

Inclusion Criteria
  • Age > 18 years.
  • Part 1 Cohort A:
    • Pathologically documented, metastatic colorectal cancer with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a Clinical Laboratory Improvement Amendments (CLIA)- certified laboratory.
    • Subjects must not have required dose reduction or been intolerant of a KRAS G12C inhibitor if they have received treatment with a KRAS G12C inhibitor in the past. A minimum of 2 subjects must be KRAS G12C inhibitor naïve per dose level.
    • Subjects must have had at least 1 prior treatment for advanced disease.
  • Part 1 Cohort B:
    • Pathologically documented, metastatic colorectal cancer with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory
    • Subjects must not have required dose reduction or been intolerant of a KRAS G12C inhibitor if they have received treatment with a KRAS G12C inhibitor in the past. A minimum of 2 subjects must be KRAS G12C inhibitor naïve per dose level.
    • If subject had received prior treatment with FOLFIRI, subjects must not have required a dose reduction for any component of the FOLFIRI regimen because of toxicity.
    • Subjects must have had at least 1 prior treatment for advanced disease.
  • Part 2 Cohort A:
    • Pathologically documented, metastatic colorectal cancer with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past
    • Subjects must have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan and an anti-angiogenic agent.
    • For those subjects with tumors known to be MSI-H, prior therapy with a CPI is required if they were clinically able to receive a CPI and 1 of these agents is approved for that indication in the region or country.
  • Part 2 Cohort B:
    • Pathologically documented metastatic advanced solid tumor with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory. 
    • Subjects must not have been intolerant of a KRAS G12C inhibitor in the past.
    • If subject previously required sotorasib dose reduction, the subject may be eligible with medical monitor approval, if the investigator assesses that treatment may be beneficial, and if the previous dose reduction was for toxicity that may not be due to sotorasib in the investigator’s opinion.
    • Subjects must have progressed on or within 2 months of last dose of KRAS G12C inhibitor.
    • Subjects must have had at least 1 prior treatment for advanced disease, and at least 1 of the prior treatments must have included a KRAS G12C inhibitor.
  • Part 2 Cohort C:
    • Pathologically documented, metastatic NSCLC with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past
    • Subjects must have had at least 1 prior treatment for advanced disease.
  • Part 2 Cohort D:
    • Pathologically documented, metastatic CRC with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified
      laboratory.
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past.
    • Subjects must have received 1 and no more than 1 prior regimen for metastatic disease.
  • Part 2 Cohort E (BID Dosing):
    • Pathologically documented, metastatic colorectal cancer with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory.
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past.
    • Subjects must have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan and an anti-angiogenic agent.
    • For those subjects with tumors known to be MSI-H, prior therapy with an anti-PD1 therapy is required if they were clinically able to receive an anti-PD1 therapy and 1 of these agents is approved for that indication in the region or country.
  • Part 2 Cohort H:
    • Pathologically documented, metastatic pancreatic cancer with KRAS p.G12C mutation identified through molecular testing
      performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory 
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past
    • Subjects must have had at least 1 prior treatment for metastatic disease
    • Neoadjuvant or adjuvant therapy will count as a line of therapy for metastatic disease if the subject progressed on or within 6 months of completion of neoadjuvant or adjuvant therapy administration.
  • Part 2 Cohort F:
    • Pathologically documented, metastatic CRC with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified
      laboratory
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past
    • Subjects may not have received any prior systemic therapy for metastatic disease.
  • Part 2 Cohort G:
    • Pathologically documented, metastatic CRC with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified 
      laboratory
    • Subjects may not have received treatment with a KRAS G12C inhibitor in the past
    • Subjects must have received at least one prior systemic therapy for metastatic disease.
  • 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.
Exclusion Criteria
  • Primary brain tumor
  • Active brain metastases and/or carcinomatous meningitis from non-brain tumors. Subjects who have had brain metastases 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.
  • History or presence of hematological malignancies unless curatively treated with no evidence of disease > 2 years
  • Myocardial infarction within 6 months of study day 1
  • Gastrointestinal (GI) tract disease causing the inability to take oral medication
  • Known positive test for human immunodeficiency virus (HIV)
  • History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis
  • Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose < 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
  • Has an active infection requiring systemic therapy.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04185883

Contact Us About This Trial

Reach out to us by sharing your info in the form below or give us a call at 972-566-3000.

Re: MC# 19-37