Study of PF-07263689 in Participants With Selected Advanced Solid Tumors

• PF-07263689 (Biological): Genetically engineered oncolytic vaccinia virus
• Sasanlimab (Biological): A monoclonal antibody that blocks the interaction between PD-1 and PD-L1/ PD-L2

Primary outcomes

• Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) [Up to 28 days]: DLTs=occurrence of any of following adverse events (AEs) attributable to PF-07263689 in first cycle (cycle=28 days): Hematologic: grade(G)4 neutropenia lasting >5 days; febrile neutropenia; G3 neutropenia with infection, thrombocytopenia with bleeding; G4 thrombocytopenia. Non-hematologic: any treatment-related G>=3 toxicity; clinical events consistent with Hy's law; any G3 cytokine release syndrome (CRS) not improving to G<=2 within 72 hours despite medical management; any G4 CRC; G>=3 toxicity of any duration affecting vital organs; G4 vaccinia infection lasting >=6 days; G>=3 toxicities persisting for >3 days despite medical therapy (e.g. nausea, vomiting, diarrhea, fatigue); G >=3 rash not resolving to G<2 within 21 days with supportive measures; G>=3 lab abnormalities not controlled to G <=2 with or without appropriate medical management within 3 days; treatment-related AE inducing a delay by 2 weeks in receiving next scheduled dose; clinically important or persistent toxicities.
• Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events [From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to maximum of 10.45 months)]: An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that at any dose met 1 or more of the following criteria: resulted in death, was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; an important medical event; required inpatient hospitalization or prolongation of existing hospitalization. TEAE was defined as any adverse event that occurred during the on-treatment period, on or after the first dose of study treatment. Relatedness was based on investigator's assessment.
• Part 1: Number of Participants With Treatment Emergent Adverse Events Based on Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Grade [From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to maximum of 10.45 months)]: An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE was defined as any AE that occurred during the on-treatment period, on or after the first dose of study treatment. AEs were graded using CTCAE version 5 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
• Part 1: Number of Participants With Hematology Abnormalities by Maximum On-Treatment CTCAE Grade [From first dose of study treatment until 1 month follow-up (28+/-7) days after last dose of study treatment (up to 24 days of treatment exposure)]: Hematology abnormalities were graded using CTCAE version 5 where, grade 0=non-missing lab value outside the grading range for the corresponding lab parameter; grade 1=mild; grade 2=moderate; grade 3=severe; grade 4= life-threatening. Only those categories with non-zero values for any of the arms have been reported.
• Part 1: Number of Participants With Clinical Chemistry Abnormalities by Maximum On-Treatment CTCAE Grade [From first dose of study treatment until 1 month follow-up (28+/-7) days after last dose of study treatment (up to 24 days of treatment exposure)]: Clinical chemistry abnormalities were graded using CTCAE version 5 where, grade 0=non-missing lab value outside the grading range for the corresponding lab parameter; grade 1=mild; grade 2=moderate; grade 3=severe; grade 4= life-threatening. Only those categories with non-zero values for any of the arms have been reported.
• Part 2: Number of Participants With Treatment Emergent Adverse Events, Serious Adverse Events, Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events [From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)]: An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that at any dose met 1 or more of the following criteria: resulted in death, was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; an important medical event; required inpatient hospitalization or prolongation of existing hospitalization. TEAE was defined as any adverse event that occurred during the on-treatment period, on or after the first dose of study treatment. Relatedness was planned to be assessed by investigator.
• Part 2: Number of Participants With Treatment Emergent Adverse Events Based on Maximum CTCAE Version 5 Grade [From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)]: AEs were planned to be graded using CTCAE version 5 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
• Part 2: Number of Participants With Laboratory Abnormalities by Maximum On-Treatment CTCAE Grade [From first dose of study treatment until 35 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)]: Hematology and clinical chemistry parameters were planned to be assessed.
• Part 2: Objective Response Rate [From first dose of study treatment until CR or PR (up to 2 years)]: ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) and was determined using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 millimeter \[mm\] short axis), PR: at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.

Secondary outcomes

• Part 1: Objective Response Rate [From first dose of study treatment until CR or PR (up to maximum follow-up of 10.45 months)]: ORR was defined as the percentage of participants with a best overall response of CR or PR and was determined using RECIST version 1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. 95% confidence interval (CI) was based on Clopper-Pearson method.
• Part 1: Duration of Response [From first documentation of CR or PR to date of first documentation of PD or death due to any cause (up to maximum follow-up of 10.45 months)]: Duration of response was defined as the time from first documentation of CR or PR to date of first documentation of progressive disease (PD) or death due to any cause. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non- pathological in size (<10 mm short axis), PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions.
• Part 1: Progression Free Survival [From start date of treatment to the date of first documentation of PD or death due to any cause (up to maximum follow-up of 10.45 months)]: Progression free survival was defined as time from start date of treatment to the date of first documentation of PD or death due to any cause. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions. 95% CI was based on Brookmeyer and Crowley method.
• Part 1: Time to Progression [From start date of treatment to the date of first documentation of PD (up to maximum follow-up of 10.45 months)]: Time to progression was defined as the time from start date of treatment to the date of the first documentation of PD. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions. 95% CI was based on Brookmeyer and Crowley method.
• Part 1: Maximum Observed Concentration (Cmax) of PF-07263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 1: Time to Maximum Concentration (Tmax) of PF-07263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 1: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration of PF-07263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 1b: Trough Concentration of Sasanlimab [pre-dose on Day 1, 8, 15 and 22]
• Part 1: Viral Titers in Saliva, Urine and Skin Swabs During 30, 45 and 60 Days After the Last PF-07263689 Dose [At 30, 45 and 60 days post last dose of study treatment (up to 24 days of treatment exposure)]: Viral titers in each matrix (saliva, urine and skin swabs \[30 days post last dose only\]) at 30, 45 and 60 days after last dose of study treatment is reported in this outcome measure.
• Part 1: Percentage of Participants With Positive Neutralizing Antibodies Against PF-07263689 and Sasanlimab [From Baseline (pre-dose) on Day 1 up to Day 22]: A participant was considered NAb positive if (1) baseline titer was missing or negative and participant had >= 1 post-treatment positive titer (treatment-induced) or (2) positive titer at baseline and had a ratio of >= 4 in titer (dilution) to baseline in >= 1 post-treatment sample (treatment-boosted). Percentage of participants with positive neutralizing antibodies against PF-07263689 is presented in this outcome measure. Data was not collected for sasanlimab as no participants were enrolled in Part 1b of the study.
• Part 1: Percentage of Participants With Positive Anti-interleukin 2 Antibodies [From Baseline (pre-dose) on Day 1 up to Day 22]: A participant was considered anti-drug antibody (ADA) positive if (1) baseline titer was missing or negative and participant had >= 1 post-treatment positive titer (treatment-induced) or (2) positive titer at baseline and had a ratio of >= 4 in titer (dilution) to baseline in >= 1 post-treatment sample (treatment-boosted). Percentage of participants with positive anti-interleukin 2 antibodies against PF-07263689 is presented in this outcome measure.
• Part 2: Maximum Observed Concentration (Cmax) of PF-7263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 2: Time to Maximum Concentration (Tmax) of PF-07263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 2: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration of PF-07263689 in Blood [Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose)]
• Part 2: Trough Concentration of Sasanlimab [Pre-dose on Day 1, 8, 15 and 22]
• Part 2: Viral Titers in Saliva, Urine and Skin Swabs During 30, 45 and 60 Days After the Last PF-07263689 Dose [30, 45 and 60 days after the last PF-07263689 dose]
• Part 2: Percentage of Participants With Positive Anti-drug Antibodies Against PF-07263689 and Sasanlimab [From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years)]
• Part 2: Titer for Anti-PF-07263689 Antibody [From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years)]
• Part 2: Percentage of Participants With Positive Anti-interleukin 2 Antibodies [From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years)]
• Part 2: Titer for Anti-IL2 Antibodies [From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years)]
• Part 2: Disease Control Rate [From start of study treatment until CR, PR or SD (up to 2 years)]: Disease control rate was the percentage of participants with CR, PR or stable disease (SD), as defined by RECIST 1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. SD: Does not qualify for CR, PR, or progression. All target lesions assessed.
• Part 2: Duration of Response [From first documentation of CR or PR to date of first documentation of PD or death due to any cause (up to 2 years)]: Duration of response was defined as the time from first documentation of CR or PR to date of first documentation of progressive disease (PD) or death due to any cause. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non- pathological in size (<10 mm short axis), PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions.
• Part 2: Progression Free Survival [From start date of treatment to the date of first documentation of PD or death due to any cause (up to 2 years)]: Progression free survival was defined as time from start date of treatment to the date of first documentation of PD or death due to any cause. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions.
• Part 2: Time to Progression [From start date of treatment to the date of first documentation of PD (up to 2 years)]: Time to progression was defined as the time from start date of treatment to the date of the first documentation of PD. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm and unequivocal progression of pre-existing lesions.
• Part 2: Overall Survival [From start of study treatment to the date of death from any cause (up to 2 years)]: Overall survival was defined as the duration from the start of study treatment to the date of death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histological or cytological diagnosis of locally advanced or metastatic solid tumors known to have approved therapies using immune checkpoint inhibitors or anti-vascular endothelial growth factor agents
* Have exhausted (or refuse) all available standard of care therapy (e.g., including anti-PD1/programmed death ligand 1 \[PDL1\] if applicable) or for whom no standard therapy is available for their tumor type
* Patients with prior anti-PD1/PDL1 must have documentation of primary or secondary resistance to last prior anti-PD1/PDL1 therapy according to Immunotherapy Resistance Committee (SITC) (Kluger et al, 2020)
* Have at least 1 measurable lesion by RECIST 1.1 that has not been previously irradiated (for Part 2 only)
* Have recently obtained archival tumor tissue sample available, or undergo de novo tumor biopsy
* Eastern Cooperative Oncology Group (ECOG) PS 0-1
* Adequate hematologic, renal, and liver functions
* Dose Escalation (Part 1A and 1B): Any advanced or metastatic solid tumor fulfilling other relevant eligibility criteria.
* Dose Expansion (Part 2): Tumor specific cohorts (NSCLC, RCC, melanoma, MSS CRC) must have received prior approved therapies (Part 2)

Exclusion Criteria:

* Other active malignancy
* Recent major surgery
* Systemic anticancer therapy and chemotherapy within protocol-defined washout period
* Known or suspected hypersensitivity to prior treatment with any vaccinia oncolytic, pox virus, or antiviral agents within the past 10 years
* Current or history of myocarditis or congestive heart failure (New York Heart Association \[NYHA\] III-IV); unstable angina; or serious uncontrolled arrhythmia or recent myocardial infarction
* Active or history of interstitial lung disease (ILD)/pneumonitis
* Patients requiring chronic systemic immunosuppressants
* History of severe immune mediated side effect that was considered related to prior immune modulatory therapy and requiring immunosuppressive therapy
* Known symptomatic brain metastases requiring steroids
* History of or ongoing severe inflammatory skin conditions or severe eczema having required medical treatment
* Any prior or planned organ transplant
* Presence of any open, active wound requiring treatment

Participant flow

Outcome results

• Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) (Primary), Count of participants, Participants: Part 1A PF-07263689 2*10^8 PFU 0; Part 1A PF-07263689 6*10^8 PFU 0; Part 1A PF-07263689 20*10^8PFU 0
• Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events (Primary), Count of participants, Participants: Part 1A PF-07263689 2*10^8 PFU 3; Part 1A PF-07263689 6*10^8 PFU 4; Part 1A PF-07263689 20*10^8PFU 6
• Part 1: Number of Participants With Treatment Emergent Adverse Events Based on Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Grade (Primary), Count of participants, Participants: Part 1A PF-07263689 2*10^8 PFU 3; Part 1A PF-07263689 6*10^8 PFU 2; Part 1A PF-07263689 20*10^8PFU 1
• Part 1: Number of Participants With Hematology Abnormalities by Maximum On-Treatment CTCAE Grade (Primary), Count of participants, Participants: Part 1A PF-07263689 2*10^8 PFU 2; Part 1A PF-07263689 6*10^8 PFU 2; Part 1A PF-07263689 20*10^8PFU 3
• Part 1: Number of Participants With Clinical Chemistry Abnormalities by Maximum On-Treatment CTCAE Grade (Primary), Count of participants, Participants: Part 1A PF-07263689 2*10^8 PFU 3; Part 1A PF-07263689 6*10^8 PFU 3; Part 1A PF-07263689 20*10^8PFU 4
• Part 2: Number of Participants With Treatment Emergent Adverse Events, Serious Adverse Events, Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events (Primary)
• Part 2: Number of Participants With Treatment Emergent Adverse Events Based on Maximum CTCAE Version 5 Grade (Primary)
• Part 2: Number of Participants With Laboratory Abnormalities by Maximum On-Treatment CTCAE Grade (Primary)
• Part 2: Objective Response Rate (Primary)
• Part 1: Objective Response Rate (Secondary), Number, Percentage of participants: Part 1A PF-07263689 2*10^8 PFU 0 (0.0 to 70.8); Part 1A PF-07263689 6*10^8 PFU 0 (0.0 to 70.8); Part 1A PF-07263689 20*10^8PFU 0 (0.0 to 60.2)
• Part 1: Duration of Response (Secondary)
• Part 1: Progression Free Survival (Secondary), Median, Months: Part 1A PF-07263689 2*10^8 PFU 1.4 (1.4 to NA); Part 1A PF-07263689 6*10^8 PFU 1.5 (1.3 to NA); Part 1A PF-07263689 20*10^8PFU 1.4 (1.4 to NA)
• Part 1: Time to Progression (Secondary), Median, Months: Part 1A PF-07263689 2*10^8 PFU 1.4 (1.4 to NA); Part 1A PF-07263689 6*10^8 PFU 1.5 (1.3 to NA); Part 1A PF-07263689 20*10^8PFU 1.4 (1.4 to NA)
• Part 1: Maximum Observed Concentration (Cmax) of PF-07263689 in Blood (Secondary), Geometric mean, Copies per milliliter: Part 1A PF-07263689 2*10^8 PFU NA +/- NA; Part 1A PF-07263689 6*10^8 PFU NA +/- NA; Part 1A PF-07263689 20*10^8PFU NA +/- NA
• Part 1: Time to Maximum Concentration (Tmax) of PF-07263689 in Blood (Secondary), Median, Hours: Part 1A PF-07263689 2*10^8 PFU NA (NA to NA); Part 1A PF-07263689 6*10^8 PFU NA (NA to NA); Part 1A PF-07263689 20*10^8PFU NA (NA to NA)
• Part 1: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration of PF-07263689 in Blood (Secondary), Geometric mean, Hours*copies per milliliter: Part 1A PF-07263689 2*10^8 PFU NA +/- NA; Part 1A PF-07263689 6*10^8 PFU NA +/- NA; Part 1A PF-07263689 20*10^8PFU NA +/- NA
• Part 1b: Trough Concentration of Sasanlimab (Secondary)
• Part 1: Viral Titers in Saliva, Urine and Skin Swabs During 30, 45 and 60 Days After the Last PF-07263689 Dose (Secondary), Mean, Copies per milliliter: Part 1A PF-07263689 2*10^8 PFU NA +/- NA; Part 1A PF-07263689 6*10^8 PFU NA +/- NA; Part 1A PF-07263689 20*10^8PFU
• Part 1: Percentage of Participants With Positive Neutralizing Antibodies Against PF-07263689 and Sasanlimab (Secondary), Number, Percentage of participants: Part 1A PF-07263689 2*10^8 PFU 66.7; Part 1A PF-07263689 6*10^8 PFU 50.0; Part 1A PF-07263689 20*10^8PFU 100.0
• Part 1: Percentage of Participants With Positive Anti-interleukin 2 Antibodies (Secondary), Number, Percentage of participants: Part 1A PF-07263689 2*10^8 PFU 0.0; Part 1A PF-07263689 6*10^8 PFU 25.0; Part 1A PF-07263689 20*10^8PFU 0.0
• 14 more outcome measures not shown.

Adverse events

Time frame: All-cause mortality: From first dose of study treatment until death, withdrawal of consent, or end of the study (up to maximum follow-up of 10.45 months); SAEs and non-SAEs: From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to maximum of 10.45 months).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Data was not collected for Part 1B and Part 2 as no participants were enrolled due to early termination.

• Study Protocol (PDF, 2021-07-20)
• Statistical Analysis Plan (PDF, 2023-03-29)

• Pfizer CT.gov Call Center, Study director, Pfizer