A Phase II Trial of MOnaliZumab in Combination With durvAlumab (MEDI4736) for tReatmenT of Small Cell Lung Cancer (MOZART)
This study has 2 cohorts: MOZART-ES cohort (for extensive-stage SCLC) and MOZART-LS cohort (for limited-stage SCLC). MOZART-ES cohort: Study treatment will consist of a platinum drug (carboplatin or cisplatin per investigator's choice) plus etoposide plus durvalumab plus monalizumab every 3 weeks for 4 cycles. After 4 cycles, subjects will continue maintenance treatment with durvalumab plus monalizumab every 4 weeks until disease progression, unacceptable toxicity, decision to stop study treatment, or withdrawal of consent. Patients who have received one prior cycle of treatment before enrolling on the study will receive a total of 4 cycles with monalizumab, durvalumab, and chemotherapy. There will be a safety lead-in phase, including 6 to 12 patients, to confirm the safety of the proposed dose of monalizumab to use in combination with chemotherapy and durvalumab. MOZART-LS cohort: Study treatment will consist of durvalumab and monalizumab following standard of care chemo-radiation consisting of a platinum drug (carboplatin or cisplatin per investigator's choice) plus etoposide for 3-4 cycles and standard dose radiation. Radiation therapy should have started before completion of cycle 2 of chemotherapy. NOTE: Subjects who have non-progressive disease and meet the eligibility criteria can start study treatment up to 56 days from completion of chemo-radiation. Durvalumab and monalizumab will be administered every 4 weeks for up to 2 years (26 cycles), disease progression, unacceptable toxicity, decision to stop study treatment, or withdrawal consent, whichever occurs first.
• Written informed consent and HIPAA authorization for release of personal health information prior to registration. Note: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Demonstrate adequate organ function. All screening labs to be obtained within 28 days prior to registration.
‣ Absolute Neutrophil Count (ANC) \> 1500mm\^3
⁃ Hemoglobin ≥ 9 g/dL
⁃ Platelet Count (PLT) ≥ 100,000 per mm3
⁃ Calculated creatinine clearance ≥ 40 mL/min
⁃ Bilirubin ≤ 1.5 × upper limit of normal (ULN); subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), may be allowed with sponsor-investigator approval.
⁃ Apsartate aminotransferase (AST) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
⁃ Alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
• Females of childbearing potential must have a negative serum pregnancy test at screening.
• Females of childbearing potential and male subjects must be willing to abstain from heterosexual intercourse or to use an effective method(s) of contraception.
• Life expectancy of ≥ 12 weeks.
• Patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable through PCR to be eligible for this trial. Testing is not required for screening unless mandated by local authorities. Local guidelines for testing should be followed.
∙ Extensive Stage Specific Inclusion Criteria:
• Histologically or cytologically confirmed diagnosis of small cell lung cancer:
• \- Extensive disease (American Joint Committee on Cancer Stage (8th edition) IV SCLC \[T any, N any, M1 a/b\]), OR T3-4 disease due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan.
• No prior systemic therapy for small-cell lung cancer, with the following exceptions: Up to one cycle of platinum doublet chemotherapy with or without durvalumab is allowed up to 4 weeks prior to registration on this study. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab and monalizumab may be included only after consultation with the sponsor-investigator. Patients should not have received Trilaciclib.
• Measurable disease according to RECIST v1.1.
• Subjects with treated brain metastasis or untreated asymptomatic brain metastasis that is clinically stable per investigator discretion and not requiring systemic steroids for ≥ 7 days. NOTE: Prophylactic cranial radiation (PCI) is allowed per investigator's discretion.
• ECOG Performance Status of 0-2.
∙ Limited Stage Specific Inclusion Criteria:
• Histologically or cytologically confirmed diagnosis of small cell lung cancer:
• \- Limited-stage disease (American Joint Committee on Cancer Stage (8th edition) I-III SCLC \[T any, N any, M0\])
• Has received platinum (cis- or carboplatin) and etoposide chemotherapy (4 cycles preferred; 3 cycles allowed if disease control is achieved and no additional benefit is expected with an additional cycle of chemotherapy in the opinion of the investigator) administered concurrently with radiation (60-66Gy daily or 45Gy BID). Radiation should have started no later than end of cycle 2 of chemotherapy.
• Non-progressive disease following completion of chemo-radiation.
• No evidence of brain metastasis. NOTE: PCI is allowed per investigator's discretion.
• Ability to start study treatment within 56 days of completing chemo-radiation, counting from whichever ends later
• ECOG Performance Status of 0-1.