IRB Study Number 25-786
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
This study aims to evaluate the safety and efficacy of olomorasib, a KRAS G12C inhibitor, in combination with pembrolizumab or durvalumab in participants with non-small cell lung cancer (NSCLC). Participants will receive combination treatment for up to 1 year, followed by monotherapy with olomorasib or placebo for a total treatment duration of up to 3 years. Transition to monotherapy is allowed earlier if clinically indicated. Short-term follow-up begins when participants discontinue study intervention, while long-term follow-up continues until loss to follow-up, study completion, or participant death.
Eligible participants must be at least 18 years old, have confirmed NSCLC with specific biomarkers (KRAS and PD-L1), and be able to perform light daily activities and swallow oral medication. Exclusion criteria include certain tumor types, EGFR or ALK gene mutations, recent active treatment for another cancer, or unresolved severe immune-related side effects from previous immunotherapy.
Part A will enroll approximately 400 participants with Stage II-IIIB NSCLC treated with chemotherapy and surgery, while Part B will enroll 300 participants with Stage III NSCLC treated with chemotherapy and radiation. Participants will be randomized in a 1:1 ratio to receive either olomorasib or placebo in combination with pembrolizumab (Part A) or durvalumab (Part B).
The study is designed to balance potential risks and benefits, with robust measures in place to minimize risks. The anticipated benefits of olomorasib-based combination therapy for early-stage KRAS G12C-mutant NSCLC are considered to outweigh the risks. A Data Monitoring Committee will oversee the study to ensure participant safety and data integrity.
Inclusion Criteria
Part A and B
- Are an acceptable age to provide informed consent according to local regulations and are at least 18 years of age.
- Have histological or cytological confirmation of NSCLC.
- Have evidence of KRAS G12C mutation in samples from tumor or blood, as determined by molecular testing performed in a CLIA, ISO/IEC, CAP, or similarly certified laboratory per local guidelines, including, but not limited to IVDR compliance, as applicable.
- Have known PD-L1 expression (0% to 100%) of tumor cells as determined by an IHC assay performed in a CLIA, ISO/IEC, CAP, or similarly certified laboratory as per local guidelines, including, but not limited to IVDR compliance, as applicable.
- Have an ECOG performance status of 0 or 1.
- Have adequate organ and marrow function as defined in the table below.
Note: Transfusions to increase a participant’s hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet these criteria are not allowed in the 14 days before the first dose of study intervention.
Test Result
Hematology
Absolute neutrophil count: ≥ 1.0 x 10ꝰ/L (≥ 1.0 x 10³/uL or ≥ 1.0 GI/L). Must be met without -CSF therapy within the last 14 days.
Platelet: ≥ 75 x 10ꝰ/L (≥ 75 x 10³/uL or ≥ 75 GI/L)
Hemoglobin Level: ≥ 8.0 g/dL or ≥ 5 mmol/L. Must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 14 days.
Clinical Chemistry
ALT and AST: ≤ 2.5 X ULN
TBL: < 1.5 x ULN or direct bilirubin within normal limits for participants with total bilirubin levels > 1.5 x ULN. For patients with Gilbert’s syndrome, total bilirubin may be > 1.5 x ULN, however direct bilirubin must be normal
Renal
Serum creatinine or measured creatinine clearance or calculated creatinine clearance or GFR or institutional standards: ≤ 1.5 x ULN or ≥ 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN. Note: Use Cockcroft-Gault CrCl formula to calculate creatinine clearance or institutional standards.
- Have recovered from any previous surgical procedure before randomization.
- Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For the contraception requirements of this protocol, see Section 10.4.
- Individuals assigned female at birth must have evidence of post-menopausal status, or individuals of child-bearing potential must have a negative pregnancy test (serum test is preferable) result at screening and have a negative serum or urine test result 72 hours before treatment with study intervention. See Section 10.4.1 for definitions of childbearing potential and menopausal status.
- Are able to swallow oral medication.
- Are capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Part A Only: Stage II-IIIB Disease, Resectable – Inclusion criteria
- Have Stage II-IIIB (N2) NSCLC per AJCC 9th edition (Rami-Porta et al. 2024) including either:
a. Clinical Stage II-IIIB (N2) treated with presurgical chemoimmunotherapy, with residual tumor present at time of surgery. Patients with a pathologic complete response are not eligible.
b. Pathologic Stage II-IIIB (N2) NSCLC treated with initial upfront resection.
- Had curative intent resection defined as lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. En bloc resection, for example, chest wall resection, or sub-anatomic resection, such as wedge resection or segmentectomy, is only permitted if performed in addition to any of the previously listed curative intent resections.
a. Must undergo complete resection, defined as pathologic microscopic margin free of invasive carcinoma at the parenchyma, bronchus, and vascular margins. Carcinoma in situ can be present at bronchial margin.
b. A systematic complete mediastinal lymph node dissection or a lobe-specific mediastinal lymph node dissection is recommended (See Section 10.7). It is recommended that normal appearing lymph nodes, if present, be biopsied or removed.
- Have no evidence of disease recurrence at clinical examination and baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 28 days before the first dose of study intervention.
- Prior treatment with chemotherapy required. Prior treatment with immune checkpoint inhibitor allowed but must be in combination with chemotherapy in the neoadjuvant setting.
a. Patients treated with presurgical therapy must receive platinum-based chemotherapy with an immune checkpoint inhibitor before randomization.
b. Patients treated initially with surgery must receive adjuvant platinum-based chemotherapy before randomization. These patients must begin adjuvant chemotherapy within 12 weeks of their surgery date. These patients must also be eligible to receive their first dose in this study at least 3 weeks but no more than 12 weeks from the last dose of adjuvant chemotherapy (Day 1 of last cycle).
Part B Only: Stage III Disease, Unresectable – Inclusion criteria
- Have clinical Stage III, unresectable NSCLC, without progression on concurrent platinum-based chemoradiotherapy. Staging is per AJCC 9th edition (Rami-Porta et al. 2024).
- Have received at least 50% of planned platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 42 days prior to randomization.
- The final chemotherapy cycle must end prior to, or concurrently with, the final dose of radiation.
- Have received a total dose of radiation of at least 54 Gy as part of the chemoradiotherapy prior to randomization.
Exclusion Criteria
Part A and B
- Have 1 of these tumor types
• large cell neuro-endocrine cancer
• mixed small cell and non-small cell lung cancer
• 2 synchronous primary invasive NSCLC in different ipsilateral or contralateral lobes.
Note: Concurrent minimally invasive adenocarcinoma (<5mm), in situ carcinoma, low grade carcinoid tumorlets are not an exclusion
• recurrent NSCLC
Have a known EGFR mutation or ALK rearrangement.
Have a known malignancy that is progressing or required active treatment within the past 3 years before screening.
Exceptions: These conditions are allowed, if already successfully treated
• non-melanomatous skin cancer
• carcinoma in situ of the cervix
• ductal carcinoma in situ of the breast
• high grade prostatic intraepithelial neoplasia (Gleason score 6/ Grade Group 1)
• non-muscle-invasive bladder cancer, not associated with high risk for progression,
or
• have received or are receiving adjuvant hormone therapy for breast or prostate cancer with no evidence of disease.
Have current or a history of non-infectious pneumonitis or interstitial lung disease that requires steroids.
Have an active uncontrolled infection requiring systemic therapy.
Had an allogenic tissue or solid organ transplant.
Have an active autoimmune disease that required systemic treatment in the past 2 years. Examples of systemic treatment includes the use of disease modifying agents, corticosteroids, or immunosuppressive drugs.
Exception: Endocrine replacement therapy is allowed. Examples include thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency.
- Has a diagnosis of primary immunodeficiency or is receiving systemic steroid therapy (dose more than 10 mg daily of prednisone equivalent) or any form of immunosuppressive therapy within 7 days prior to first dose of study intervention.
Exception: corticosteroid premedication for contrast allergy is allowed.
Have active or prior documented inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis.
Have a known history of HIV infection (HIV-1 or HIV-2 antibody positive). HIV testing is not required unless required by local health authorities.
Have a history of or current infection with HBV under one of the following conditions
• patients with positive HBsAg or detectable HBV DNA who are not receiving HBV prophylaxis with a NA initiated at least 7 days prior to first dose of study intervention
• patients with HBV DNA > 1000 IU/mL
• patients with positive HBsAg, or anti-HBc, or detectable HBV DNA, who are unable to undergo monitoring of HBsAg, HBV DNA, and liver tests (ALT, AST, ALP, TBL, GGT) at least every 3 months.
Have a current infection with HCV, defined as positive for HCV RNA.
Have a known history of active tuberculosis.
Have clinically significant active cardiovascular disease or history of myocardial infarction or unstable angina within 6 months prior to planned start of study.
Have a 12-lead ECG QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 msec. If QTcF >470 msec on 1 ECG is obtained during the screening, obtain 2 additional measurements and use the average of the 3 measurements to determine eligibility.
Exception: Individuals with implanted pacemakers.
Have a serious preexisting medical condition that, in the judgment of the investigator, would preclude participation in this study, including but not limited to, substance use disorder, an unstable mental health disorder, severe dyspnea at rest or requiring oxygen therapy. Screening for chronic conditions is not required.
Have an active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study intervention.
Have experienced any Grade ≥3 immune-related AE (irAE) or Grade ≥3 hypersensitivity while receiving any previous immunotherapy agent, or any unresolved irAE Grade >1.
Exception: Endocrinopathies on replacement hormonal therapy.
Have any other unresolved Grade >2 toxicities, except for alopecia, from prior therapy.
Received a live vaccine or live attenuated vaccines within 30 days before the first dose of study intervention.
Exception: Seasonal influenza vaccines for injection, which are generally killed virus vaccines.
Are currently enrolled in any other clinical study involving an investigational product within 4 weeks prior to the first dose of study intervention. In the case of monoclonal antibodies, 6 weeks prior to the first dose of study intervention.
Are currently enrolled in any type of medical research judged not to be scientifically or medically compatible with this study as determined by sponsor consult.
Are pregnant, breastfeeding, or plan on becoming pregnant or breastfeeding during the study or within 180 days after the last dose of study intervention.
Part A Only
For patients treated with upfront surgical resection, have received more than 4 cycles of adjuvant chemotherapy
For patients treated with presurgical chemo-immunotherapy, have received any adjuvant therapy
Part B Only
Have received non-standard of care treatment regimens, such as induction chemotherapy plus immunotherapy followed by concurrent chemoradiation therapy.
Have received sequential chemotherapy followed by radiation therapy
Have Grade ≥ 2 pneumonitis from prior chemoradiation therapy
