IRB Study Number 24-103
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the efficacy of durvalumab plus tremelimumab plus chemotherapy compared with pembrolizumab plus chemotherapy in terms of OS, in participants with non-squamous histology who have metastatic NSCLC with mutations and/or co-mutations in STK11, KEAP1, or KRAS.
To assess the efficacy of durvalumab plus tremelimumab plus chemotherapy compared with pembrolizumab plus chemotherapy in terms of OS, in participants with non-squamous histology who have metastatic NSCLC with STK11 or KEAP1 mutations and/or co-mutations.
Secondary Objectives
To further assess the efficacy of durvalumab plus tremelimumab plus chemotherapy compared with pembrolizumab plus chemotherapy in terms of OS, PFS, ORR, DoR and TFST, in participants with non-squamous histology who have metastatic NSCLC with mutations and/or co-mutations in STK11, KEAP1, or KRAS.
Inclusion Criteria
Age
1 Participant must be ≥ 18 years at the time of signing the ICF.
Type of Participant and Disease Characteristics
2 Histologically or cytologically documented Stage IV non-squamous NSCLC not amenable to curative surgery or radiation.
3 Participants must have tumors with STK11 or KEAP1 or KRAS mutations. Co-mutations are also allowed (STK11 and KRAS mutations, STK11 and KEAP1 mutations, or KEAP1 and KRAS mutations).
4 Participants must have tumors that lack activating EGFR mutations (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, exon 20 insertions, or exon 20 S768I mutation) and ALK fusions.
5 No prior chemotherapy or any other systemic therapy for metastatic NSCLC. Participants who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy (see exclusion criterion 15).
6 No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anti-cancer vaccines, within 12 months to randomization.
7 WHO/ECOG performance status of 0 or 1 at enrollment and randomization.
8 Minimum life expectancy ≥ 12 weeks at randomization.
9 At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have a short axis ≥ 15 mm) with CT/CT-PET or MRI and that is suitable for accurate repeated measurements (as per RECIST 1.1 guidelines).
10 Adequate organ and bone marrow function:
Hemoglobin ≥ 9.0 g/dL without transfusion 4 weeks prior to the screening and randomization.
Absolute neutrophil count ≥ 1.5 × 109/L.
Platelet count ≥ 100 × 109/L.
Total bilirubin ≤ 1.5 × ULN.
Total bilirubin ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia).
ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN.
Calculated CrCL > 40 mL/min as determined by co*ckcroft Gault (using actual body weight).
Males: CrCL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)
Females: CrCL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL) × 0.85 Weight
11 Body weight of > 30 kg
Sex and Contraceptive/Barrier Requirements
12 Male and/or female.
Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix F for further details.
(a) Male participants:
Male participants who intend to be sexually active with a female partner of child-bearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix F) from the time of screening throughout the total duration of the study and the drug washout period (up to 11 months after the last dose of cisplatin or 90 days after tremelimumab or durvalumab or pembrolizumab or pemetrexed, whichever is longer; and during treatment with carboplatin) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.
(b) Female participants:
Negative pregnancy test (urine or serum) for women of child-bearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). Women of child-bearing potential must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to within 14 months after the last dose of cisplatin or 180 days after pemetrexed or 90 days after tremelimumab or durvalumab or pembrolizumab, whichever is longer; and during treatment with carboplatin (see Appendix F for complete list of highly effective birth control methods). Non-sterilized male partners of a woman of child-bearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period.
Informed Consent
13 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
Other Inclusion Criteria
14 All races, genders, and ethnic groups are eligible for this study.
Exclusion Criteria
Medical Conditions
1 As judged by the Investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhea, psychiatric illness/social situations), chronic diverticulitis or previous complicated diverticulitis (with the exception of diverticulosis), or history of allogenic organ transplant, which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
2 Mixed small cell lung cancer and NSCLC histology.
3 Major surgical procedure (excluding placement of vascular access), as defined by the Investigator, within 28 days prior to the first dose of the study intervention or an anticipated need for major surgery during the study. Note: Local surgery of isolated lesions for palliative intent is acceptable.
4 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis [requiring immunosuppressive systemic therapy, eg, methotrexate, steroids], hypophysitis, uveitis, etc), autoimmune pneumonitis and autoimmune myocarditis. The following are exceptions to this criterion:
Participants with vitiligo or alopecia.
Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
Any chronic skin condition that does not require systemic therapy.
Participants without active disease in the last 5 years may be included but only after consultation with the Study Clinical Lead.
Participants with celiac disease controlled by diet alone.
5 Medical contraindication to platinum-based doublet chemotherapy.
6 History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
7 Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy (see inclusion criterion 5), alopecia and vitiligo are excluded toxicities. Participants with Grade ≤ 2 neuropathy can be considered based on Investigator’s judgement. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with study intervention in the opinion of the Investigator may be included (eg, hearing loss).
8 Spinal cord compression unless asymptomatic and stable A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and study enrolment.
9 History of leptomeningeal carcinomatosis.
10 Known to have tested positive for active TB infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or TB testing in line with local practice).
11 Known active hepatitis infection, positive HCV antibody, HBsAg, or anti-HBc, at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA); AND
HCV positive (presence of anti-HCV antibodies); OR
HDV positive (presence of anti-HDV antibodies).
12 Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load for 6 months, CD4+ count of > 500 cells/μL), stable for at least 6 months on the same anti-HIV medications, and no history of AIDS (either CD4+T cell count < 200 cells/μL and/or AIDS-defining opportunistic infection.
13 Participant meets the following:
Symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended.
Prior/Concomitant Therapy
14 Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
15 No radiation therapy is allowed, unless it is 1) definitive radiation that had been administered at least 6 months prior, 2) palliative radiation to brain, with associated criteria for stability or lack of symptoms (see also exclusion criterion 16), or 3) palliative radiation to painful bony lesions (this must comprise less than 30% of the bone marrow).
16 Brain metastases. Patients with suspected brain metastases at screening should have an intravenous (IV) contrast-enhanced MRI (preferred) or IV contrast-enhanced CT/CT-PET of the brain prior to study entry. If brain metastases are detected patients must be treated before randomization. Randomization is only permitted if patients with brain metastases have:
Confirmed stable condition
Returned neurologically to baseline
Brain metastases will not be recorded as RECIST target lesions at baseline.
17 Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication, premedication for chemotherapy) or a single dose for palliative purpose (eg, pain control).
18 Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention (see Appendix G).
Prior/Concurrent Clinical Study Experience
19 Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
20 Participants with a known hypersensitivity to any of the study interventions or any of the excipients of the products.
Other Exclusions
21 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
22 Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
23 For females only: Currently pregnant (confirmed with positive pregnancy test) or breast-feeding, or who are planning to become pregnant. Female participants should refrain from breastfeeding from enrolment throughout the study and until up to 14 months after the last dose of cisplatin or 180 days after pemetrexed or 90 days after tremelimumab or durvalumab or pembrolizumab, whichever is longer; and during treatment with carboplatin.
