Symbiotic-Lung-14: A Study to Learn About the Study Medicine called PF-08634404 in Combination With Chemotherapy in Adult Participants With Transformed Small Cell Lung Cancer

Prior treatment

• Participants with known active CNS lesions, including brainstem, meningeal, or spinal cord metastases or compression are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be enrolled if all of the following are met: • CNS metastases have been clinically stable with no evidence of clinical or radiographic disease progression for ≥14 days after completion of definitive radiotherapy (or ≥7 days for stereotactic radiosurgery) and/or surgery and prior to study intervention. • The participant has not required steroids for brain metastasis symptom management for 7 days prior to first dose of study intervention. Participants with untreated asymptomatic brain metastases are permitted if all of the following criteria are met: • absence of neurological symptoms • no need for corticosteroids, and • brain metastasis has no evidence of mass effect or hemorrhagic features
• Major surgery or severe trauma within 4 weeks prior to the first dose, or planned major surgery during the study; minor local surgery (excluding peripherally inserted central catheter placement and implantable central venous port placement) within 3 days prior to the first dose. Participants must have recovered adequately from the toxicity or complications from the surgery prior to starting study intervention.
• History of severe bleeding tendency or coagulation dysfunction, such as presence of clinically significant bleeding symptoms within 1 month prior to the first dose, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing up or expectorating ≥½ teaspoon of fresh blood or small blood clots or coughing up blood without sputum; participants with blood-streaked sputum are allowed to be enrolled), or epistaxis (excluding minor nosebleeds and blood-tinged nasal discharge).
• History of esophageal varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to the first dose;
• For participants who have been previously exposed to PD-(L)-1 inhibitors: a) History of Grade 3 or higher irAEs (excluding endocrine system-related irAEs) caused by immunotherapy, irAEs leading to permanent discontinuation of treatment, Grade 2 immune-related cardiotoxicity, or irAEs of any grade affecting the nervous system or eyes. b) All adverse events from prior immunotherapy have not completely resolved or have not improved to Grade 1 before screening for this study. Participants with endocrine system-related adverse events Grade ≥2 may be enrolled if they are stable on appropriate replacement therapy and asymptomatic. c) History of adverse events requiring treatment with immunosuppressants other than corticosteroids, or recurrence of adverse events during prior immunotherapy necessitating systemic corticosteroid therapy again.
• Previous administration of an investigational product (drug or vaccine) within 30 days or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during participation in this study.
• Clinically significant risk of hemorrhage or fistula including but not limited to the following: a) Significant tumor necrosis or cavitation, b) The investigator deems that participation in the study poses a risk of hemorrhage; c) Tumor invasion or compression of surrounding critical organs (such as aorta, heart and pericardium, superior vena cava, trachea, and esophagus) or a risk of developing tracheoesophageal or pleuroesophageal fistula; • Has radiographic evidence of major blood vessel invasion/infiltration, eg, main pulmonary artery, left and right pulmonary arteries, the 4 major pulmonary veins, the superior or inferior vena cava, and the aorta. Note: The degree of proximity to major blood vessels should be considered because of the potential risk of hemorrhage associated with tumor shrinkage/necrosis following study intervention. d) Mediastinal lymph node metastasis with invasion of the trachea or main bronchi. If centrally located mediastinal masses identified by CT scan or chest x-ray, CT scan with intravenous contrast or MRI within 28 days prior to enrollment must exclude major airway or blood vessel invasion by tumor.
• Unresolved toxicities from prior antitumor therapy, that did not recover to NCI CTCAE v5.0 Grade 0 or 1, or to levels specified in the inclusion/exclusion criteria, with the exception of alopecia. Participants who experience irreversible toxicity that is not expected to worsen with continued administration of the study intervention (eg, hearing loss) may be enrolled in the study after the medical monitor will be informed. Participants with long-term toxicity from radiotherapy that is deemed irreversible by the investigator may be enrolled in the study Information should be provided to the medical monitor before proceeding.
• Participants with active autoimmune diseases requiring systemic treatment within the past 2 years prior to first dose of study intervention (ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs) a) Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic disease modifying treatment and is allowed. b) Participants with vitiligo, psoriasis, type 1 diabetes mellitus (if not excluded per exclusion criterion 9i), or resolved childhood asthma/atopy are allowed. c) Participants requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections are allowed (if not excluded per exclusion criterion 8c). d) Participants with Sjögren’s syndrome are allowed (if not excluded per exclusion criterion 8c).
• Participants with any of the following respiratory conditions: a) Evidence of non-infectious or drug-induced ILD or pneumonitis that: • Was previously diagnosed and managed with parenteral steroids for any duration or oral steroids for >6 weeks, or • Had onset during or after treatment with immunotherapy, improved or resolved, then recurred after immunotherapy rechallenge, or • Is currently diagnosed and managed with systemic therapy, or • Is suspected on radiologic imaging at screening. • Participants who are asymptomatic and have radiographic findings of noninfectious, radiation-induced, or drug-induced ILD or pneumonitis confined to 1 bronchopulmonary segment or <10% of lung parenchyma may be enrolled after the medical monitor is informed. b) Any Grade ≥3 pulmonary disease unrelated to underlying malignancy including, but not limited to: • Severe asthma requiring systemic corticosteroids within 30 days prior to first dose of study intervention or not well controlled with low-dose inhaled corticosteroids/long-acting beta-2 agonists. • Severe chronic obstructive pulmonary disease requiring supplemental oxygen or systemic corticosteroids. • Clinically severe and/or Grade 4 pulmonary emboli within 3 months of the first dose of study intervention. Pulmonary emboli in main or lobar pulmonary arteries are also excluded. For thromboembolic events other than pulmonary emboli please refer to Exclusion Criterion 9k. • Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc).

Other illness

• Participants with history of immunodeficiency
• Known to have a history of a severe allergic reaction including anaphylaxis or CTCAE Grade ≥3 hypersensitivity reactions to any active substance or excipients of the study interventions, or a history of severe allergic reaction to chimeric or humanized antibody.
• Leptomeningeal disease
• Participants with any history of another malignancy (other than NSCLC) within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

Lab values

• Participants with acute, chronic or symptomatic infections including: a) Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of enrollment. Routine antimicrobial prophylaxis is permitted. b) Known seropositivity of HIV, except for participants with controlled HIV infection on a stable regimen of ART (CD4+ count >200/mm3 and viral load of <400 copies/mL). The investigator will ensure the ART does not result in substantial interactions with study or concomitant medications. c) Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 2 weeks and have undetectable HBV viral load or HBV-DNA <1000 copies/ml (200 IU/ml), whichever is lower, prior to randomization. Note: participants with chronic hepatitis B (anti-HBc and HBsAg positive) should receive anti-hepatitis B virus therapy during study treatment.Active HCV infection (positive by PCR). Participants who have been treated for HCV infection are eligible if they have documented sustained virologic response 12 weeks after completion of antiviral therapy. d) Testing for HIV, HBV, or HCV is not required unless mandated by local health authorities. e) Participants with known active TB infection • participants suspected of having active TB are required to undergo clinical evaluation to rule out the condition;
• Any medical or psychiatric condition including any active suicidal ideation in the past year or suicidal behavior in the past 5 years or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
• Previous systemic anti-tumor therapy including: a) Anti-angiogenic agents targeting VEGF, its receptor or other specific molecules involved in angiogenesis. b) Prior radiotherapy >30 Gy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received. c) Palliative local therapy within 2 weeks before the first dose; d) Non-specific immunomodulatory therapy (such as interleukin, interferon, thymosin, tumor necrosis factor, excluding IL-11 for thrombocytopenia treatment) within 2 weeks before the first dose. Note: Previous systemic anti-tumor therapy for NSCLC with chemotherapy and immunotherapy is allowed. Participant must have failed TKI(s) for EGFR mutant NSCLC.
• Prior and concomitant therapy: a) Use of therapeutic oral or parenteral anticoagulants within 10 days prior to the first dose (excluding use of anticoagulants as secondary prophylaxis); note: Full-dose oral or parenteral anticoagulants are permitted if the INR or aPTT is within the therapeutic range and the participant has been on a stable dose of anticoagulants for at least 2 weeks prior to the first dose. Prophylactic use of anticoagulants for secondary prophylaxis is permitted. b) Use of chronic systemic antiplatelet therapy, including aspirin, dipyridamole, clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. Participants with concurrent use of NSAIDs who, in the judgment of the investigator, are at increased risk of bleeding or GI perforation are excluded. c) Use of any live or attenuated live vaccine within 4 weeks prior to the first dose, or planned vaccination of any live or attenuated live vaccine during the study. d) Current use of a high-dose systemic corticosteroids (>10 mg daily prednisone or equivalent) or other immune suppressant or has a condition requiring a chronic high-dose steroid or immune suppressant. e) Use of any prohibited concomitant medication(s) within 21 days of the first dose of study intervention or unwillingness or inability to use a required concomitant medication(s). Refer to Section 6.9.
• History of uncontrolled comorbidities within 6 months prior to the first dose including but not limited to the following: a) Unstable angina b) Myocardial infarction c) Uncontrolled or significant arrhythmia (including sustained ventricular tachyarrhythmia and ventricular fibrillation), untreated serious conduction system abnormalities (eg, bifascicular block [defined as right bundle branch and left anterior or posterior hemiblock], 3rd degree AV block) d) Coronary/peripheral artery bypass graft e) Transient ischemic attack, cerebrovascular accident, cerebral infarction (excluding lacunar infarction), or cerebral hemorrhage f) Symptomatic congestive heart failure or symptoms consistent with NYHA Functional Class III or IV g) Decompensated liver cirrhosis h) Nephrotic syndrome i) Uncontrolled diabetes defined as HbA1c ≥8.0% or HbA1c between 7.0% and 8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained (or poor compliance with hypoglycemic medications) j) Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg, or poor compliance with antihypertensive medications) k) Arterial thromboembolic event and venous thromboembolic event Grade >3 as specified in CTCAE 5.0 l) Hypertensive crisis m) Hypertensive encephalopathy n) Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN)

Other

• Baseline QTcF interval > 480 msec • If QTcF exceeds 480 msec, the ECG should be repeated twice and the average of the 3 QTcF values should be used to determine the participant’s eligibility. Computer-interpreted ECGs with abnormal findings should be overread by an investigator physician experienced in reading ECGs before excluding participants.
• Participants with pleural effusion, pericardial effusion, or ascites that are clinically symptomatic or require repeated drainage (once a month or more frequently).
• Other circumstances that may increase the study-related risks or interfere with interpretation of the study results, in the opinion of the investigator.
• Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
• Breastfeeding participants; participants of childbearing potential and male participants who are unwilling to follow pregnancy measures.

• 18 years of age or older (or the minimum age of consent in accordance with local regulations) at screening.
• Histologically or cytologically confirmed T-SCLC. Participant must have had a prior diagnosis of NSCLC with EGFR mutation which transformed to SCLC following the treatment with TKI(s). Patients with transformed SCLC after therapy for NSCLC with mutations other than EGFR will be excluded. Participants with a history of NSCLC without AGAs or with squamous histology will also be excluded.
• Participants have not received systemic therapy for T-SCLC. Participants who received a single cycle of chemotherapy (without immune checkpoint inhibitors) for the management of life-threatening T-SCLC symptoms (such as superior vena cava syndrome but no cord compression)), as determined by the investigator, prior to enrollment confirmation may be eligible.
• Have at least one measurable lesion as the target lesion based on RECIST v1.1. Lesions treated after prior local treatment (radiotherapy, ablation, interventional procedures, etc.) are generally not considered as target lesions. If the lesion with prior local treatment is the only target lesion, evidence-based radiology must be provided to demonstrate disease progression (a single bone metastasis or a single central nervous system metastasis should not be considered as a measurable lesion).
• Have sufficient tumor tissue from the diagnosis of transformed SCLC available, either paraffin block or slides from a core, excisional or fine needle biopsy (FNA cytology samples which have not been prepared as an FFPE block, and biopsies containing bone are not adequate). a) Archival specimen from the most recent biopsy before the start of study intervention. See Central Laboratory Manual for tissue specifications, handling, and shipping instructions. b) If sufficient archival tissue is not available, a new baseline tumor biopsy with adequate tissue is required, unless medically infeasible. c) In addition to required T-SCLC tissue, submission of archival NSCLC tissue taken prior to diagnosis of T-SCLC is optional but highly encouraged.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Have a minimum life expectancy of ≥12 weeks.
• Have adequate organ function, as defined below: a) Participants must meet the hematologic criteria below in Table 5 without the use of transfusions or growth factors (platelet or red blood cell transfusions, TPO, EPO, G-CSF, IL-11, etc.) within 7 days prior to screening laboratory tests.
• The participant must provide written informed consent.