| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer Subjects with KRASG12C Mutation After Failure of Prior Standard Therapies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer Subjects with KRASG12C Mutation After Failure of Prior Standard Therapies |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To evaluate the antitumor effects of RMC-4630 and sotorasib in locally advanced or metastatic NSCLC subjects with KRASG12C mutation with and without coexisting genetic aberrations in specific genes such as STK11/LKB1, KEAP1, and PIK3CA after failure of prior standard therapy |
|
| E.2.2 | Secondary objectives of the trial |
1- To characterize the safety, tolerability, and PK of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy
2- To further characterize efficacy of RMC-4630 in combination with sotorasib as assessed by DOR, DCR, PFS, and OS in subjects with KRASG12C mutant locally advanced or metastatic NSCLC after failure of prior standard therapy
Exploratory
• To explore PK relationships with safety and/or efficacy endpoints
• To investigate potential biomarkers by biochemical and/or genetic analysis of blood and/or tumor tissue samples |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be ≥18 years of age at the time of signing the informed consent form (ICF).
2. Subject must have pathologically documented, locally advanced or metastatic KRASG12C
NSCLC (not amenable to curative surgery) that has progressed on prior standard therapies (no more than 3 prior lines of therapies are allowed), as follows:
a. Subject with actionable oncogenic driver mutations (eg, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase [ALK], and ROS1) must have received standard-of-care anticancer treatments, including approved drugs for oncogenic drivers in their tumor type.
b. Subject’s tumor must harbor a KRASG12C mutation assessed by a CLIA-/CAP-certified laboratory.
3. Subject must have measurable disease per RECIST v1.1, criteria.
4. Subject must have a life expectancy of at least 3 months.
5. The subject’s ECOG PS of 0 to 1 with no deterioration in PS 2 weeks prior to C1D1. Rescreening is required if PS is >1 for any reason prior to C1D1.
6. Subject must have the ability to typically ingest and retain PO medications.
7. Subject must have adequate hematological and biological function, as follows:
a. Bone marrow function:
i. Absolute neutrophil count (ANC) ≥1.5 × 109/L without use of hematopoietic growth factors
ii. Hemoglobin ≥9 g/dL; subject must not have received a red blood cell (RBC) transfusion within 28 days of Screening
iii. Platelets ≥100 × 109/L; subject must not have received a platelet
transfusion within 14 days of Screening
b. Subject must have hepatic function as follows:
i. AST and ALT ≤2.5 × upper limit of normal (ULN)
ii. Bilirubin ≤1.5 × ULN (<2.0 × ULN for subject with documented Gilbert’s
syndrome or <3.0 × ULN for subject for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
c. Subject must have renal function as follows: Serum creatinine ≤1.5 × ULN or creatinine clearance (CrCl) of >50 mL/min (using the Cockcroft-Gault formula or 24-hour urine collection)
d. Subject must have coagulation function as follows: Prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) <1.3 × ULN, or within target range if taking prophylactic anticoagulant(s).
8. Female subject is eligible to participate if she meets the following criteria:
a. Is not a woman of childbearing potential (WOCBP), OR
b. Is a WOCBP and using a contraceptive method that is highly effective (ie, with a failure rate of <1% per year), preferably with low user dependency, during the treatment period and for at least 2 months after the last dose of study treatment and agree not to donate eggs (ie, ova and oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. Hormonal contraception efficacy may potentially be decreased due to interaction with sotorasib; therefore, male condoms must be used in addition to any hormonal-based contraception methods.
9. Male subject is eligible to participate if he agrees to the following during the treatment period and for ≥3 months after the last dose of study treatment:
a) Refrains from donating sperm (any donation of sperm should be conducted prior to study start) PLUS, either:
b) Abstain from intercourse as his preferred and usual lifestyle (abstinent on a longterm and persistent basis) and agree to remain abstinent, OR
c) Must agree to use a male condom AND should also be advised of the benefit for a nonpregnant female partner to use a highly effective method of contraception as a condom may break or leak
10. Subject is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
11. Subject must provide unstained, archived, tumor tissue samples collected within the past 3 years. Subjects who do not have archived tissue available are required to undergo a tumor biopsy. |
|
| E.4 | Principal exclusion criteria |
Subjects with:
1.Primary central nervous system tumor(s)
2 Have known or suspected leptomeningeal or brain metastases or spinal cord compression. However, a subject who was previously treated for these conditions who have had stable CNS diseases are eligible to participate in the study, as long as stable disease is documented by a brain MRI performed within 28-days (D) of C1D1.
3 Have any of the following cardiac abnormalities:
a Medically uncontrolled hypertension,
b Congestive heart failure Class ≥2,
c Acute coronary syndrome; myocardial infarction within 6M of ICF,
d History or evidence of current, uncontrolled, clinically significant, unstable arrhythmias: i Subject with medically controlled atrial fibrillation >1M prior to Study Day 1 is eligible. ii Subject who has a pacemaker in place to control atrial arrhythmias is a candidate for the study.
e History of congenital long QT syndrome or prolonged corrected QT interval (QTc) >470 msec for females and > 450 msec for males using Fridericia’s formula or uncorrectable abnormalities in serum electrolytes: i Subject may use average of triplicate readings for assessing QTc interval. ii Subject with an implantable defibrillator is not eligible to participate in the study
f Current cardiomyopathy or history within in the past 12M prior to ICF
g Baseline left ventricular ejection fraction below the institutional lower limit
of normal or <50%, whichever is lower.
4 Any prior history of (or active) ILD or pneumonitis, or prior thoracic radiotherapy within 2M of enrollment.
5 Subject has a history or current evidence of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or predisposing factors to RPED or RVO
6 Visible retinal pathology as assessed on ophthalmic examination that is considered a significant risk factor for RVO or RPED by ophthalmologist
7 Have of Grade ≥2 proteinuria
8 Have a history of cerebrovascular accident or transient ischemic attack previous 6M of signing the ICF
9 Have a known activating SHP2 mutation
10 Have an active autoimmune disease requiring systemic treatment within the past 2 years of signing the ICF; includes current autoimmune sequelae or previous Grade >2 autoimmune sequelae from checkpoint inhibitors or other immunomodulatory treatments that require systemic therapy. Subject with autoimmune endocrine disorder on hormonal supplementation may be enrolled, even if Grade >2 upon initial presentation,
11 Have known HIV infection
12 Have an active/chronic hepatitis B or C virus infection
13 Have a known impairment of gastrointestinal function that may significantly alter the absorption of RMC-4630
14 Have a history of severe allergic reactions
15 Have major surgical procedures ≤28 D or non-study-related minor procedures ≤7D prior to Cycle 1 Day 1 (C1D1)
16 Have any clinically significant concurrent medical condition that would, in the opinion of the investigator, and/or impact their ability to comply with the protocol. Any subject who had a pulmonary embolism within 3M of C1D1 will also be excluded.
17 Have had prior therapy with one or both of the following agents, meets criteria for exclusion: a KRASG12C inhibitor and b. SHP2 inhibitor
18 Have had treatment with chemotherapy or biologics/monoclonal antibodies <21D or 5 half-lives before C1D1
19 Have had treatment with non-thoracic radiation therapy <14D before C1D1
20 Have had treatment with tyrosine kinase inhibitor (TKI), hormonal therapy <7D before C1D1
21 Have had treatment with immunotherapy 14-21D before C1D1, depending on cycle length of drug
22 Have had treatment with all other anticancer treatments including investigational agents that do not fit in the above categories <21D before C1D1
23 Require treatment with proton pump inhibitors (PPIs) or H2 receptor antagonists (H2-blockers). If an acid reducing agent cannot be avoided, administer sotorasib and RMC-4630 either 4hrs before or 10hrs after a local antacid.
24 Have had consumption of strong CYP3A4 inducers or inhibitors within 7D prior to initiation of study treatment and requires treatment with strong CYP3A4 inducers or inhibitors
25 Have had consumption of strong P-glycoprotein (P-gp) inhibitors within 7D prior to initiation of study treatment and requires treatment with a strong P-gp inhibitor
26 Use of known CYP3A4 and P-gp sensitive substrates, within 14D or 5 half-lives of the drug prior to study D1 that was not reviewed and approved by the principal investigator.
27 Have had clinically significant reversible toxicities from prior cancer therapy that have not recovered to Grade 1 or baseline, except for alopecia. Subject with Grade ≤2 neuropathies due to prior treatment will be allowed on study. Subject with other Grades ≤2 clinical nonsignificant toxicities, may be allowed on study after discussion with Medical Monitor.
28 Female who is pregnant or breastfeeding
29 Unwillingness or inability to comply with the protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate as assessed per Response Evaluation Criteria in Solid Tumours, Version 1.1; |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Incidence, nature, and severity of treatment-emergent adverse event, SAEs, clinically significant changes in laboratory tests, ECGs, and vital signs
• Trough and approximate peak concentrations of RMC-4630 and sotorasib
• duration of response, disease control rate and progression-free survival as assessed per RECIST v1.1, and overall survival
Exploratory
• Sotorasib and RMC-4630 exposure/safety and exposure/efficacy relationships
• Quantification of biomarker expression (protein, RNA, and DNA levels) as appropriate in ctDNA and archival tumor tissues (or fresh, if archival tumor is not available) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Study drug combined with Sotorasib |
|
| 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 | No |
| 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 | 25 |
| 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 |
| Australia |
| Canada |
| Germany |
| Italy |
| Korea, Republic of |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
| France |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The study duration is approximately 2 years. The End of study is defined as the date of last subject, last visit or 12 months after the last subject receives the first dose of study treatment, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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