RASolve 301

Phase 3 Multicenter, Open Label, Randomized Study of RMC-6236 versus Docetaxel in Patients with Previously Treated Locally Advanced or Metastatic RAS[MUT] NSCLC

To be included in the study, each potential patient must meet all of the following inclusion criteria.
Patient Characteristics:
1. Age: ≥ 18 years and has provided informed consent. Follow local regulatory requirement if the legal age of consent for study participation is >18 years old.
2. Performance Status: ECOG PS 0 or 1, without significant decline within 2 weeks of screening; rescreening is required if PS >1 for any reason before randomization.
Disease Characteristics:
3. NSCLC: Histologically confirmed NSCLC, either locally advanced or metastatic, not amenable to curative surgery or radiotherapy.
4. Progressive Disease: Evidence of progressive disease (PD) per RECIST v1.1 from prior therapy or intolerance to prior therapy.
5. Measurable Disease: Assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST v1.1 based on site Investigator/radiology assessment.
Irradiated lesions are not considered measurable unless they have progressed after radiation.
6. Prior Therapy: Prior therapy for advanced disease must be limited to 1 or 2 prior lines of therapy and must include an anti-PD-1/anti-PD(L)-1 agent and a platinum-based chemotherapy. Prior therapy with any RAS inhibitor, including a KRAS G12C inhibitor, is prohibited. Adjuvant therapy or multimodal therapy with curative intent is considered prior therapy if disease progression occurred on or within 6 months of treatment completion.
7. RAS Mutation: Nonsynonymous mutations in KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61). These mutations must have been previously (independent of this trial) identified in ctDNA in plasma or DNA sequence variations in tumor tissue (obtained within 5 years of consent), using approved or validated assay and performed in a CLIA-certified laboratory (US) or certified laboratory per local regulations.
8. Tumor Tissue: Patient must submit tumor tissue, as specified in Section 9.7.1, for retrospective central laboratory testing of RAS mutation status and exploratory biomarker analysis.
Organ Function:
9. Adequate Bone Marrow Function:
a. Absolute neutrophil count ≥1.5×10^9/L (without growth factor support within 7 days of screening)
b. Hemoglobin ≥9.0 g/dL (without transfusion within 2 weeks of screening)

c. Platelet count ≥100×10^9/L (without transfusion within 2 weeks of screening)
10. Adequate Kidney Function: Estimated glomerular filtration rate ≥60 mL/min, calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation or other equation per institutional guidelines, or based on 24-hour urine collection.
11. Adequate Liver Function:
a. AST and ALT ≤2.5×ULN, except if alkaline phosphatase > 2.5 times the ULN, then AST and/or ALT must be < 1.5 times the ULN
b. Serum bilirubin ≤1.0×ULN (<2×ULN for patients with documented Gilbert syndrome)
12. Adequate Coagulation Function: PT/international normalized ratio (INR) and aPTT/PTT <1.5×ULN or within target range per institutional guidelines if on anticoagulant(s)
Other Inclusion Criteria:
13. Oral Medication: Able to take oral medications and willing to keep daily adherence record.
14. Optional research study: Patients must provide separate informed consent to participate in ancillary exploratory studies. If a patient declines, there is no penalty or loss of benefit to the patient in this primary study.

To be included in the study, potential patients must not have any of the following exclusion criteria.
Disease Characteristics:
1. Previous therapy: RAS-directed therapy.
2. Other driver mutations: Epidermal growth factor receptor (EGFR) or serine/threonine protein kinase B-Raf (BRAF) mutation, anaplastic lymphoma kinase (ALK) mutation, reactive oxygen species-1 (ROS-1), tropomyosin receptor kinase (TRK) fusion, or other identifiable driver mutation for which an approved targeted therapy is available. KRAS G12C mutations, if adagrasib and/or sotorasib are available and deemed to be indicated by the Investigator.
3. Untreated CNS metastases or leptomeningeal disease: Treated CNS metastases are allowed if ALL of the following conditions are met:
a. Radiation therapy ended ≥2 weeks before randomization (stable disease confirmed by scan performed after CNS-directed treatment has been completed).
b. No evidence of clinical or radiographic progression by a CNS imaging performed within 4 weeks of randomization.
c. Stable residual neurological symptoms Grade ≤2 and on a stable dose of steroids and/or anticonvulsant therapy (if applicable) for ≥2 weeks before randomization.

4. Other Cancers: Diagnosed or treated ≤3 years before randomization, except:
a. Cancers for which no systemic anticancer treatment is required and were treated with successful definitive resection (eg, non-melanoma skin cancer, carcinoma in situ of the breast or cervix, or other in situ cancers).
b. Cancers that have been treated with curative intent judged by Investigator to have a low risk for recurrence during trial participation (eg, <5% risk of recurrence within 5 years).
5. Uncontrolled Effusion: Pleural effusion, pericardial effusion, or ascites requiring monthly or more frequent drainage procedures. Patients with a permanent catheter in place (eg, PleurX) may be permitted if considered by the Investigator to be clinically stable.
6. Ongoing non-protocol specified anticancer therapy: Anticancer therapies that have been discontinued before randomization must follow these washout periods:
a. Radiation; Radiotherapy to ≥30% of bone marrow or wide field radiation ≥4 weeks of randomization; stereotactic radiotherapy or whole brain radiotherapy ≥2 weeks of randomization.
b. Chemotherapy and Antibody Therapy; ≥3 weeks of randomization.
c. Small Molecule Targeted Therapy; ≥2 weeks or ≥5 half-lives of randomization, whichever is longer.

Note: Bisphosphonates or antireceptor activator of nuclear factor kappa beta therapy are considered supportive care and permitted.

7. Unresolved AEs from Prior Therapy: Clinically relevant toxicity associated with prior anticancer therapy that in the opinion of the Investigator has not recovered to Grade 1, baseline, normal, or to the levels dictated by the inclusion/exclusion criteria, including ongoing Grade ≥2 peripheral neuropathy according to NCI-CTCAE v5.0, except for alopecia or endocrine disorder stably maintained with appropriate replacement therapy.
Medical Disorders:
8. Significant Cardiovascular Disease:
a. Acute coronary syndrome (eg, unstable angina, myocardial infarction) within 6 months of randomization.
b. Symptomatic congestive heart failure (New York Heart Association Class II to IV) within 4 weeks of randomization.
c. Left ventricular ejection fraction <50% within 4 weeks of randomization, per echocardiography or MUGA scan.
d. QTc >470 msec, averaged from 3 ECGs, using the screening clinic ECG machine derived QTcF.
e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (eg, second-degree heart block, third-degree heart block, complete left bundle branch block, PR interval >250 msec).
f. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.

g. Patients with hypokalemia (<3 mmol/L or lower limit of normal per local laboratory) or hypomagnesemia (<0.5 mmol/L or lower limit of normal per local laboratory) must be replete to normal and receive potassium or magnesium supplementation while on study treatment.
9. Significant Lung Disease: History of interstitial pneumonia, pneumonitis, pulmonary fibrosis, or radiation pneumonitis which required steroid treatment within 6 months before randomization, or any evidence of active interstitial lung disease on screening imaging.
10. Impaired GI Function: Any conditions that may affect the ability to take or absorb oral study treatment (eg, refractory nausea and vomiting, malabsorption, significant bowel resection, or uncontrolled inflammatory GI disease such as Crohn disease or ulcerative colitis).
11. HIV, HBV, or HCV Infection: Patients with the following active infections will be excluded if any of the following conditions are met:
a. For patients with known HIV infection:
i. CD4+ T-cell counts < 350 cells/µL or a history of AIDS-defining opportunistic infection in the previous 12 months before randomization
ii. If CD4+ T-cell counts ≥ 350 cells/µL, enrollment may be considered if the patient is on established antiretroviral therapy for ≥ 4 weeks before randomization and treatment regimen does not conflict with other study restrictions, and patient has a viral load of < 400 copies/mL before randomization.
b. For patients positive for HBcAb at screening: Positive hepatitis B surface antigen or positive HBV DNA by PCR test
c. For patients positive for HCV antibody at screening: Positive HCV RNA by PCR test
12. Other Medical Conditions: Any serious medical or psychiatric condition (eg, uncontrolled hypertension, bleeding diatheses) or active infection that would pose a risk to patient safety, impair the patient’s ability to participate in the study, or jeopardize protocol compliance. Consult the Sponsor Medical Monitor to discuss.
Exclusion Criteria Related to Study Treatment:
13. Requires treatment with strong or moderate CYP3A4 inhibitors/inducers, or consumed Seville oranges, grapefruit, and grapefruit products, from 14 days before C1D1. Patients randomized to RMC-6236 must continue to refrain from such treatments/products through the EOT. Patients randomized to docetaxel must continue to refrain from strong CYP3A4 inhibitors/inducers through the EOT.
14. Requires treatment with P-gp inhibitor from 14 days before C1D1. Patients randomized to RMC-6236 must continue to refrain from such treatments through the EOT.
15. Requires treatment with sensitive or moderately sensitive or narrow therapeutic index substrate of P-gp from 7 days prior to C1D1. Patients randomized to RMC-6236 must continue to refrain from such treatments through the EOT.
16. Requires systemic treatment with cyclosporine A or derivative.

17. History of allergy or known hypersensitivity to any of the study treatments or any of their excipients, or contraindication to any of the study treatments as outlined in the local prescribing information (eg, USPI).
18. Prior treatment with docetaxel
19. History of hypersensitivity to docetaxel or to other drugs formulated with polysorbate 80
Other Exclusion Criteria
20. Life Expectancy: <3 months, in the opinion of the Investigator.
21. Major Surgery: <4 weeks of randomization.
22. Other Clinical Trials: On other therapies or participating in other trials that may interfere with the conduct or interpretation of data from the current study.
23. Pregnancy and Breastfeeding: Women with a positive pregnancy test at screening or C1D1. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during treatment and for at least 6 months after the last dose of RMC-6236 or for at least 2 months after the last dose docetaxel.
24. Childbearing or Reproduction: Women or men of childbearing or reproductive potential unwilling to use highly effective forms of contraception or avoid intercourse during treatment for the following durations after the last dose of study medication: for at least 6 months for women after the last dose of RMC-6236, for at least 2 months for women after the last dose of docetaxel, for at least 3 months for men after the last dose of RMC 6236, or for at least 4 months for men after the last dose of docetaxel. Refer to Appendix 3 for contraceptive guidance for females or WOCBP partners of male participants.
25. Egg or Sperm Donation: Women or men unwilling to abstain from donating egg or sperm during treatment and for at least 6 months (for women) or at least 3 months (for men) after the last dose of RMC-6236, or for at least 2 months (for women) or for at least 4 months (for men) after the last dose of docetaxel.
26. Noncompliance to Protocol Visits or Procedures: Patient is unable or unwilling to comply with all protocol-required study visits or procedures, in the judgment of Investigator.