assignment
Not Yet RecruitingPhase 1b/2 Study of PF-08634404 in Combination with Sigvotatug Vedotin or Other Anticancer Agents in Participants with Advanced Solid Tumors
- Trial ID
- 2025-523526-40-00
- Protocol
- C6461020
- Sponsor
- Pfizer Inc.
Trial statistics
science
3
test molecules
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22
research sites
public
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countries
medical_information
5
diseases
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24
investigators
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16
vendors
Objectives
The primary objectives of this study are to evaluate the safety and tolerability of PF-08634404 in combination with either sigvotatug vedotin or PF-08046054 during a safety run-in phase. In the dose optimization and expansion phase, the study aims to assess antitumor efficacy and to identify a recommended dose for these combination therapies in participants with advanced solid tumors. 4, 5
The secondary objectives include:
- Evaluation of preliminary antitumor efficacy during the safety run-in phase. 5
- Assessment of pharmacokinetics for the combination regimens. 6
- Evaluation of immunogenicity resulting from the administration of the combination therapies. 13
- Additional monitoring of safety and efficacy measures. 4, 5
Participants
This study involves 109 patients, including both males and females, within specific age ranges. The study population consists of individuals diagnosed with pathologically confirmed non-small cell lung cancer, classified as either locally advanced or metastatic. Participants must lack small cell elements and are excluded if they have large cell neuroendocrine carcinoma. Eligible subjects are required to have measurable disease according to RECIST v1.1 and must possess a performance status of 0 or 1 as defined by the ECOG scale. Additional requirements include a minimum expected survival of 12 weeks and adequate organ function. For specific study components, PD-L1 expression must be at a tumor proportion score of 1% or greater. Sufficient tumor tissue must be available for analysis via pathological confirmation.
Plans and Procedures
This interventional, open-label Phase 1b/2 study is designed to evaluate the safety, pharmacokinetics, and preliminary efficacy of PF-08634404 in combination with different anticancer agents in participants with advanced solid tumors. The research methodology is divided into two primary stages: a Phase 1 safety run-in to assess tolerability and identify dose-limiting toxicities, followed by Phase 2 dose optimization and dose expansion to evaluate antitumor efficacy and establish a recommended dose. The study design incorporates combinations of PF-08634404 with sigvotatug vedotin or PF-08046054. The screening visit is utilized to confirm eligibility based on criteria such as pathological diagnosis, PD-L1 status, and measurable disease according to RECIST v1.1. The trial is estimated to conclude by July 2029. Primary endpoints include the frequency and severity of adverse events and the objective response rate. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, and the incidence of immunogenicity.
Treatment
PF-08634404 is an experimental therapeutic administered as a concentrate for solution for infusion via the intravenous route.
Sigvotatug vedotin is an experimental agent provided in the form of a powder for concentrate for solution for infusion and is administered through intravenous infusion.
Humanised IgG1 monoclonal antibody against PD-L1 conjugated to monomethyl auristatin E via a valine-citrulline linker is an experimental substance supplied as a lyophilized powder for preparation for injection for intravenous administration.
Efficacy
The assessment of preliminary efficacy in participants with advanced solid tumors is conducted through several clinical endpoints. In the dose optimization and dose expansion phases, the primary efficacy endpoint is the confirmed objective response rate (ORR) as determined by the investigator according to RECIST v1.1.
Secondary efficacy parameters include:
- Disease control rate (DCR) evaluated via RECIST v1.1,
- Duration of response (DOR) assessed via RECIST v1.1,
- Progression-free survival (PFS) measured using RECIST v1.1, and
- Overall survival (OS).
Inclusion and Exclusion Criteria
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Inclusion Criteria
- 18 years of age or older (or the minimum age of consent in accordance with local regulations) at screening.
- Participants must meet the following criteria: Have pathologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) squamous or non-squamous NSCLC and are not a candidate for complete surgical resection and curative concurrent/sequential chemoradiotherapy (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer TNM staging system). Participants with locally advanced (Stage IIIB/IIIC) disease who cannot undergo radical concurrent/sequential chemoradiotherapy, per assessment by the relevant specialist physician. Mixed-type tumors will be classified by pathological type based on the predominant cell type. Must not have small cell elements present. Large cell neuroendocrine carcinoma is excluded.
- Have sufficient tumor tissue available, either paraffin block or slides from a core, excisional, or fine needle biopsy (FNA cytology samples prepared as FFPE cell blocks). FNA cytology samples not prepared as FFPE cell blocks 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.
- PD-L1 status available based on local testing results. a) Part B only: PD-L1 ≥ TPS 1% based on local testing results.
- Measurable disease based on RECIST v1.1 per investigator. Participants with prior definitive radiotherapy must have measurable disease per RECIST v1.1 that is outside the radiation field or have unequivocal progression of previously irradiated lesions.
- ECOG PS score of 0 or 1.
- Expected survival ≥12 weeks
- Adequate organ function determined by meeting the following criteria within 7 days prior to first study intervention administration: a) Participants must meet the hematologic criteria below 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.
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Exclusion Criteria
- Participants with known AGAs, including EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET, for which there are available front-line therapies per local standard of care are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.
- 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: a. CNS metastases have been clinically stable with no evidence of clinical or radiographic disease progression for ≥14 days after completion of definitive radiotherapy and/or surgery and prior to study intervention. b. The participant has not required steroids for brain metastasis symptom management for 7 days prior to first dose of study intervention. c. Participants with asymptomatic brain metastases of longest diameter <1 cm 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 edema or hemorrhagic features
- Participants with leptomeningeal metastasis
- 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; d) Mediastinal lymph node metastasis with invasion of the trachea or main bronchi. If centrally located mediastinal masses (<30 mm from the carina) identified by CT scan or chest x-ray, CT scan with intravenous contrast or MRI within 21 days prior to randomization must exclude major airway or blood vessel invasion by tumor.
- Participants with any history of another malignancy 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.
- Unresolved toxicities from prior anti-tumor 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. 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.
- History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
- Participants with active autoimmune diseases requiring systemic treatment within the past 2 years (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 10), 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 9c). d) Participants with Sjögren’s syndrome are allowed (if not excluded per exclusion criterion 9c).
- Participants with any of the following respiratory conditions: a) Evidence of non-infectious or drug-induced ILD or pneumonitis that: • Was previously diagnosed and was 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; the medical monitor should be informed before proceeding b) Known DLCO (adjusted for hemoglobin) <50% predicted. c) 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 10. • Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc).
- History of uncontrolled comorbidities within 6 months prior to the first dose including: 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
- 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 must be overread by an investigator physician experienced in reading ECGs before excluding participants.
- 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.
- Participants with pleural effusion, pericardial effusion, or ascites that are clinically symptomatic or require repeated drainage (once a month or more frequently).
- 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 recurrent 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;
- 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 randomization. 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 (see Section 10.5). c) Known to be positive for HBV by surface antigen expression. d) 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. e) Testing for HIV, HBV, or HCV is not required unless mandated by local health authorities. f) Participants with known active TB infection; participants suspected to have active TB are required to undergo clinical evaluation to rule out the condition.
- Participants with history of immunodeficiency
- Known to have a history of a severe allergy to any component of the study intervention, or a history of severe allergic reaction to chimeric or humanized antibody
- 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.
- Other circumstances that may increase the study-related risks or interfere with interpretation of the study results, in the opinion of the investigator.
- Previous systemic anti-tumor therapy, including: a) Prior systemic therapy for locally advanced, unresectable, or metastatic NSCLC. b) Previous treatment with immunotherapy, including immune checkpoint inhibitors (eg, PD-(L)-1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, anti-LAG3 antibodies), immune checkpoint agonists (eg, ICOS, CD40, CD137, OX40 antibodies), immune cell therapy, or any other treatment targeting antitumor immune mechanisms. (Neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred ≥ 9 months after the last dose Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose. c) Previous treatment with ADCs containing MMAE payload d) Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received. e) Palliative local therapy within 2 weeks before the first dose; f) 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. g) Prior systemic anti-angiogenic therapy, including but not limited to bevacizumab and its biosimilars, endostatin, small-molecule TKIs, and ramucirumab
- 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.
- Prior and concomitant therapy: a) Use of therapeutic oral or parenteral anticoagulants or thrombolytic agents within 10 days prior to the first dose (excluding prophylactic use); note: Full-dose oral or parenteral anticoagulants are permitted if the PT/INR or PTT/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 or thrombolytics is permitted. b) Use of chronic antiplatelet therapy, defined as continuous daily use of one or more antiplatelet agents for ≥3 months, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole, clopidogrel, or similar agents within 7 days prior to randomization. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. 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 highdose 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 6.9.1.
- 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.
- 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 contraceptive measures.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Apr 2026 | 10 |
 Germany | Not Yet Recruiting | 01 Apr 2026 | 6 |
 Italy | Not Yet Recruiting | 01 Apr 2026 | 16 |
 Spain | Not Yet Recruiting | 01 Apr 2026 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PF-08634404 | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD12922792 |
Sigvotatug vedotin | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD11727381 |
Conditions Studied in This Trial
Interventions Studied in This Trial
vaccines
HUMANISED IGG1 MONOCLONAL ANTIBODY AGAINST PD-L1 CONJUGATED TO MONOMETHYL AURISTATIN E VIA A VALINE-CITRULLINE LINKER
2 trials
vaccines
SIGVOTATUG VEDOTIN
3 trials