| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Solid Tumors with KRAS p.G12C Mutation |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced Solid Tumors with KRAS p.G12C Mutation |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
All subprotocols
Phase 1b
•To evaluate the safety and tolerability of investigational regimens of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors
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| E.2.2 | Secondary objectives of the trial |
All subprotocols
Phase 1b
•To characterize PK of product(s) used in investigational regimens of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors.
•To evaluate anti-tumor activity of investigational regimens of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For the full list of inclusion criteria please refer to section 5.1 of the of the subprotocols.
All subprotocols
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 coagulation laboratory assessments as follows:
•PT or PTT or activated partial thromboplastin time ≤ 1.5 x ULN, OR (INR) ≤ 1.5 x ULN or within target range if on prophylactic anticoagulation therapy.
Subprotocol F
•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 according to in-country requirements.
•Adequate hepatic laboratory assessments, as follows:
•AST and 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 (TBL) ≤ 1.5x ULN: for subjects with known Gilbert’s syndrome TBL ≤ 2.0 x ULN will be allowed if AST, ALT and direct bilirubin are within normal limits
•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
Subprotocol H
•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. (Part 1)
•Adequate hepatic laboratory assessments, as follows:
• AST ≤2.5 x ULN (if liver metastases are present, ≤5 x ULN)
• ALT ≤ 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
•Total bilirubin ≤ 1.5 x ULN for Part 1 Cohort A, Part 2 Cohorts A to E and Cohort H
•Total bilirubin ≤1 x ULN for Part 1 Cohort B and Part 2 Cohorts F, G and I
Subprotocol J:
• Pathologically documented, locally-advanced or metastatic malignancy 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. |
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| E.4 | Principal exclusion criteria |
For the full list of exclusion criteria please refer to section 5.2 of the of the subprotocols.
All sub protocols
•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 non-invasive carcinoma or carcinoma in situ.
•Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrythmia requiring medication
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 criteria:
-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 HIV
Subprotocols F,H,J:
•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
Sub protocol H,J:
Primary brain tumor
Sub protocol H:
•History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis
•Is unable to interrupt aspirin or other 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).
•Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of breast cancer receiving adjuvant hormonal therapy], or investigational agent except for sotorasib) within 28 days of study day 1. Targeted small molecule inhibitors, within 14 days of study day 1, provided at least 5 half lives have passed.
•Currently receiving treatment in another investigational device or drug study, or less than 28 days since last intervention on another investigational device or drug study(ies) with the exception of sotorasib studies, in which case, there is no requirement for minimum time from last sotorasib dose provided all sotorasib related toxicities have resolved to grade 1 or less. Other investigational procedures while participating in this study are excluded.
Subprotocol F
•Mixed small-cell lung cancer and NSCLC histology
•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.
•Is unwilling to take premedication for pemetrexed, docetaxel, or paclitaxel.
•Is unable or unwilling to take folic acid or vitamin B12 supplementation.
•Prior therapy with a KRAS G12C inhibitor.
•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. Exception: Subjects who receive prior tyrosine kinase inhibitor monotherapy within 14 days or conventional chemotherapy within 21 days of study day 1 are eligible.
Subprotocol J:
•Evidence of interstitial lung disease or active, non-infectious pneumonitis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
•Dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and clinically significant changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for this study will occur when target enrollment is complete and each subject either completes at least 6 months on study or withdraws from the study.
The final analysis will be conducted and reported following the end of the study. The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), including any additional parts in the study (eg, long‑term follow‑up), as applicable.
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| E.5.2 | Secondary end point(s) |
Phase 1b
•Pharmacokinetic parameters of product(s) including, but not limited to, maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), and area under the plasma concentration-time curve (AUC)
•Objective response (complete response[CR] + partial response [PR]),
Disease control rate, duration of response, and progression-free survival, measured by computed tomography (CT) or magnetic
resonance imaging (MRI) and assessed per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for this study will occur when target enrollment is complete and each subject either completes at least 6 months on study or withdraws from the study.
The final analysis will be conducted and reported following the end of the study. The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), including any additional parts in the study (eg, long‑term follow‑up), as applicable.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase Ib Safety, tolerability, PK, PD and efficacy - dose exploration and dose expansion |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| H -Panitumumab, FOLFIRI ; F- Carboplatin, pemetrexed, paclitaxel and docetaxel |
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| E.8.2.4 | Number of treatment arms in the trial | 21 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Taiwan |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Germany |
| Italy |
| Netherlands |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (i.e., last subject last visit), including any additional parts in the study (e.g., long-term follow-up [LTFU],), as applicable. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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