MC# 19-37 - Subprotocol L: A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Sotorasib in Combination with BI 1701963 in Subjects with Advanced Solid Tumors with KRAS p.G12C Mutation

  • Agent(s): Sotorasib & BI 1701963
  • Disease Type(s): Colorectal, Solid Tumor, Lung-NSCLC
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): KRAS G12C

Mechanism of Action

Sotorasib selectively targets the KRAS p.G12C mutant, and prevents expression of and/or tumor cell signaling through the KRAS p.G12C mutant. This inhibits 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.

BI 1701963 selectively targets and binds to SOS1, preventing the interaction of SOS1 with KRAS. This prevents activation of downstream RAF/MEK/ERK signaling pathway by GTP-loaded KRAS. This inhibits mutant KRAS-dependent signaling and may inhibit growth and survival of KRASexpressing tumor cells.


In this study, the sponsor and investigators want to learn:

  • How much of sotorasib can be given with an acceptable level of side effects alone and in combination with BI 1701963
  • The effects of sotorasib (good and bad) alone and in combination with BI 1701963
  • How much of sotorasib is absorbed into the blood and how fast it is removed
Inclusion Criteria
  • Subject has provided informed consent prior to initiation of any study specific activities/procedures
  • Male and female subjects age ≥ 18 years old
  • Pathologically documented, locally advanced or metastatic malignancy, with KRAS p.G12C mutation identified through molecular testing, who are intolerant or ineligible, to available therapies known to provide clinical benefit:
    • For NSCLC, subjects must have received anti-PD-1 or anti-PD (L)-1 therapy (unless contraindicated) and/or platinum-based combination chemotherapy and targeted therapy (if actionable oncogenic driver mutations were identified [eg, EGFR, ALK, and ROS1]). Prior neoadjuvant/adjuvant chemotherapy or chemoradiation will be considered for eligibility only if the subject progressed on or within 6 months of completing the therapy. KRAS p.G12C mutation must be identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC. In the United States, this test must be performed in a local Clinical Laboratory Improv ement Amendments certified laboratory.
    • For CRC, all subjects must have received at least 1 prior systemic regimen of therapy for advanced or metastatic CRC including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. In addition, subjects with tumors that are MSI-H must have received treatment with either nivolumab or pembrolizumab if they were clinically able to receive checkpoint inhibitors and 1 of these agents is approved for that indication in the region or country
    • For advanced solid tumor types other than NSCLC and CRC, subjects must have received at least 1 prior systemic therapy
    • Subjects who have received prior KRAS p.G12C targeted therapy must have progressed
  • Subjects must be willing to undergo tumor biopsy before start of treatment, if medically feasible, unless a sample is available within 3 months of enrollment without intervening treatment. If a tumor biopsy prior to treatment is not medically feasible and recent sample is not available, or if the biopsy sample has insufficient tissue for testing, subjects must be willing to provide archived tumor tissue samples (FFPE sample) collected within the past 3 years, if available. Subjects who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not feasible.
  • Measurable disease per RECIST v1.1 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 products
  • Corrected QT interval (QTc) ≤ 470 ms for females and ≤ 450 ms for males (based on average of screening triplicates)
  • Adequate hematological laboratory assessments (without transfusion or growth factor support within 2 weeks of assessment), 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 calculation ≥60 mL/min/1.73 m2
  • Adequate hepatic laboratory assessments, as follows:
    • AST < 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN)
    • ALT < 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
    • Total bilirubin (TBL) < 1.5 x ULN (< 2.0 x ULN for subjects with documented Gilbert’s syndrome or < 3.0 x ULN for subjects for whom the indirect BIL level suggests an extrahepatic source of elevation, with medical monitor approval)
  • Adequate coagulation laboratory assessments, as follows:
    • Prothrombin time (< 1.5 x ULN) or international normalized ratio (< 1.5 or within target range if on prophylactic anticoagulation), and (activated) partial thromboplastin time < 1.5 x ULN.
Exclusion Criteria
  • Primary brain tumor
  • Spinal cord compression or active brain metastases or leptomeningeal disease from non-brain tumors. Subjects who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade ≤ 2; and, b) on stable or decreasing doses of dexamethasone, if applicable. In addition, if treatment was completed > 4 weeks prior to study entry MRI performed within 4 weeks prior to study entry must show no new or enlarging lesions appearing.
  • History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years. Note: indolent malignancies that do not currently require treatment are allowed.
  • 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 or low risk prostate cancer in active surveillance or watchful waiting
    • Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ
  • Inadequate cardiac function:
    • Myocardial infarction within 6 months of study day 1
    • Congestive heart failure (CHF; New York Heart Association > class II)
    • Unstable angina
    • Poorly controlled arrhythmia
    • Left ventricular ejection fraction <50%, or clinically significant findings on electrocardiogram (ECG)
    • Congenital long QT syndrome
    • Uncontrolled hypertension, defined as: blood pressure (BP) measured in a rested and relaxed condition, where systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg consistently, with or without medication in 3 consecutive measurements
  • History of RPED or RVO
  • Gastrointestinal tract disease causing the inability to take or absorb oral medication, malabsorption syndrome, requirement for intravenous (IV) alimentation, uncontrolled inflammatory GI disease (eg, Crohn’s disease, ulcerative colitis)
  • Evidence of hepatitis infection based on the following results and/or criteria:
    • Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B)
    • Negative HepBsAg with a positive test 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 is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C and needs exclusion.
  • Positive test for human immunodeficiency virus (HIV)
  • History of non-infectious pneumonitis or ILD, including checkpoint inhibitor induced pneumonitis, or any evidence of clinically active ILD
  • History of lung conditions that increase risk for pneumonitis or ILD including active autoimmune disease with pulmonary component, radiation of lung/thorax > 30 Gy within the last 6 months, active tuberculosis, or pneumonia
  • History of severe allergic reactions to any of the study intervention components
  • Prior anti-tumor therapy (antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of breast cancer receiving adjuvant hormonal therapy], or investigational agent) within 28 days of study day 1. Note: subjects who receive prior targeted small molecule inhibitors or conventional chemotherapy within 14 days of study day 1 are excluded, including subjects who received prior KRAS p.G12C inhibitor monotherapy within 14 days.
  • Therapeutic radiation within 4 weeks of study day 1 or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
  • Use of known cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator (PI) and the Amgen Medical Monitor.
  • Use of strong inducers and inhibitors of CYP3A4 (including herbal supplements such as St. John’s wort) and P-gp within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the PI and the Amgen Medical Monitor.
  • Active infection requiring intravenous (IV) antibiotics within 1 week of study enrollment (day 1)
  • Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to 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, neuropathy, or endocrinopathies controlled with hormone replacement 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
  • Subjects who had to discontinue sotorasib previously due to toxicity
  • Subject unable to receive both iodinated contrast for CT scans and gadolinium contrast for MRI scans
  • Any dose reduction, ≥ grade 3 treatment-related adverse event, or treatment discontinuation for any adverse event related to the previous treatment with KRAS p.G12C inhibitor (only for subjects enrolled in Part 1)
  • Major surgical procedures ≤ 28 days or non–study-related minor procedures ≤ 7 days prior to C1D1. In all cases, the subjects must be sufficiently recovered and stable before treatment administration.
  • Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
  • Subjects who had to discontinue sotorasib previously due to toxicity
  • Female subjects of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an
    additional 7 days after the last dose of sotorasib and for an additional 4 months after the last dose of BI 1701963
  • Female subjects who are breastfeeding or who plan to breastfeed while on study through 7 days after the last dose of sotorasib and 4 months after the last dose of BI 1701963
  • Female subjects planning to become pregnant while on study through 7 days after the last dose of sotorasib and 4 months after the last dose of BI 1701963
  • Female subjects of childbearing potential with a positive pregnancy test assessed at screening by a highly sensitive urine or serum pregnancy test
  • Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib and for an additional 4 months after the last dose of BI 1701963.
  • Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib and for an additional 4 months after the last dose of BI 1701963
  • Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of sotorasib and for an additional 4 months after the last dose of BI 1701963
  • Subject has known sensitivity to any of the products or components to be administered during dosing
  • Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge
  • History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 19-37