A Phase 1 Open-Label Study of PF-07934040 as a Single Agent and in Combination With Other Targeted Agents in Participants With Advanced Solid Tumors Harboring Mutations in the KRAS Gene
- Histological or cytological diagnosis of advanced, unresectable, and/or metastatic or relapsed/refractory solid tumor. ECOG PS 0 or 1
- Presence of at least 1 measurable lesion based on RECIST version 1.1 that has not been previously irradiated.
- Documentation of mutated KRAS gene 1. PDAC, CRC, Other tumor types: Confirmed KRAS mutation, any variant 2. NSCLC: Confirmed KRAS mutation, any variant except previously treated G12C. If driver mutation, must have failed precision medicine therapy \[eg, inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and others\].
- Part 1 and Part 2a: Participant must have progressed on standard treatment(s) for which no additional, effective therapy is available. 1. PDAC (2-3L): Participants must have received and radiologically progressed on prior lines of systemic therapy for metastatic pancreatic adenocarcinoma. If participants received prior neoadjuvant or adjuvant chemotherapy and progressed within 6 months of the last dose, then this should be considered as a prior line of systemic therapy. 2. NSCLC (2-3L): Participants must have received prior lines of anti-cancer treatment and progressed on at least a platinum-containing chemotherapy regimen and checkpoint inhibitor therapy; for participants with EGFR, ALK, or other genomic tumor alterations, participants must have progressed on approved therapy for these alterations. 3. CRC (2-3L): Participants must have had one or two prior systemic treatment regimens for mCRC. For either one or two prior treatments, these regimens must have included a fluoropyrimidine, oxaliplatin, or irinotecan; for one prior treatment, exposure to VEGF/VEGF receptor (VEGFR) inhibitor is optional; 4. Other tumors: Participants, in the judgment of the investigator, must have progressed or become intolerant to all available standard therapies, or have refused such therapy.
- Part 2b: 1. PDAC (1L) Cohort A2: Participants must not have received prior chemotherapy for metastatic disease. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy, as long as relapse did not occur within 6 months of completing these forms of adjuvant treatment. If so, the relapse within 6 months would be considered a line of therapy; the participant would be considered 2L, and not 1L. 2. CRC (2-3L) Cohort B2: Participants must have had one or two prior systemic treatment regimens for mCRC. For either one or two prior treatments, these regimens must have included a fluoropyrimidine, irinotecan, oxaliplatin; for one prior treatment, exposure to a VEGF/VEGF receptor (VEGFR) inhibitor is optional. 3. CRC (1L) Cohort B3: Participants must not have had prior chemotherapy for advanced or metastatic disease. Participant could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy, as long as relapse did not occur within 6 months of complete of adjuvant therapy. If so, the relapse within 6 months would be considered a line of therapy; the participant would be considered 2L, and not 1L. 4. NSCLC (1L) Cohort C2: Participants must have a TPS ≥50% and must not have received prior systemic treatment setting. 5. NSCLC (1L) Cohort C3: Participants with any TPS and must not have received prior systemic treatment setting.
- Active or history of pneumonitis/ILD, pulmonary fibrosis requiring treatment with systemic steroid therapy, including evidence to suggest pneumonitis/ILD on baseline assessments including imaging.
- Diagnosis of immunodeficiency or an active autoimmune disease that require systemic treatment with chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy in the past 2 years.
- Sensory peripheral neuropathy ≥Grade 2
- Active or history of clinically significant gastrointestinal (GI) disease (including but not limited to inflammatory GI disease \[eg, ulcerative colitis, Crohn's disease, inflammatory bowel disease\], immune-mediated colitis, peptic ulcer disease, GI bleeding, chronic diarrhea) and other conditions that are unresolved and/or may increase the risk associated with study participation or study treatment administration.
- Active bleeding disorder, including GI bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 6 months.
- Major surgery or completion of radiation therapy ≤4 weeks prior to enrollment/randomization or radiation therapy that included \>30% of the bone marrow.
- Known sensitivity or contraindication to any component of study intervention (PF 07934040, gemcitabine, nab-paclitaxel, cetuximab, bevacizumab, FOLFOX, 5-FU, pembrolizumab, cisplatin, carboplatin, pemetrexed, SHP2 inhibitor(s), cyclin-dependent kinase (CDK) inhibitor(s), antibody drug conjugates (ADCs) or EGFR inhibitor(s)).
- Hematologic abnormalities.
- Renal impairment.
- Hepatic abnormalitie
Participant Group/Arm
EXPERIMENTAL: Part 1
PF-07934040 Monotherapy Dose Escalation PF-07934040 monotherapy at prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2a Cohort A1
Monotherapy dose expansion in 2-3L PDAC. PF-07934040 at prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2a Cohort B1
Monotherapy dose expansion in 2-3L CRC. PF-07934040 at prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2a Cohort C1
Monotherapy dose expansion in 2-3L NSCLC. PF-07934040 at prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2b Cohort A2
Combination (PF-07934040 + Gemcitabine + Nab-paclitaxel) dose escalation/expansion in 1L PDAC. Prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2b Cohort B2
Combination (PF-07934040 + Cetuximab) dose escalation/expansion in 2-3L CRC Prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC Prescribed dose and frequency in 28-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2b Cohort C2
Combination (PF-07934040 + Pembro) dose escalation/expansion in 1L NSCLC (TPS ≥ 50%) Prescribed dose and frequency in 21-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Participant Group/Arm
EXPERIMENTAL: Part 2b Cohort C3
Combination (PF-07934040 + Pembro + Platinum Chemo) dose escalation/expansion in 1L NSCLC (any TPS) Prescribed dose and frequency in 21-day cycles
Intervention/Treatment
DRUG: PF-07934040
panKRAS inhibitor
Outcome Measure
Part 1 & 2: Incidence of Adverse Events (AEs)
Measure Description
An adverse event (AE) was any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship to it. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. AEs included both serious and all non-serious AEs.
Time Frame
Start of treatment up to 30 days after last dose or start of new anticancer therapy (whichever occurs first)
Outcome Measure
PART 1 & 2: Number of participants with laboratory abnormalities
Measure Description
Number of participants with laboratory test abnormalities. Laboratory test parameters included hematology, coagulation, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy).
Time Frame
From start of treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first
Outcome Measure
Part 1: Number of participants with Dose-limiting toxicities (DLT)
Measure Description
Any of the prespecified AEs that are attributable to one, the other, or both study treatments, occurring in the DLT observation period are considered DLTs, excluding toxicities clearly due to underlying disease or extraneous causes
Time Frame
Baseline up to 28 days
Outcome Measure
Part 2: Objective Response - Number of Participants With Objective Response (alone or in combination)
Measure Description
Percentage of participants with objective response-based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for overall response rate (ORR), progression free survival (PFS), and overall survivor (OS) assessed by the Investigator.
Time Frame
Baseline and every 8 to 12 weeks through time of confirmed disease progression, death, unacceptable toxicity, or through study completion, approximately 2 years'
Outcome Measure
Part 1 & 2: Maximum Observed Serum Concentration (Cmax)
Measure Description
Evaluate the single and multiple dose PK of PF-07934040 as monotherapy, or in combination with other anti-tumor agents.
Time Frame
baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days)
Outcome Measure
Part 1& 2: Time to Reach Maximum Observed Serum Concentration (Tmax)
Measure Description
Evaluate the single and multiple dose PK of PF-07934040 as monotherapy, or in combination with other anti-tumor agents.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days)
Outcome Measure
Part 1 & 2: Serum Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Measure Description
Evaluate the single and multiple dose PK of PF-07934040 as monotherapy, or in combination with other anti-tumor agents.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days)
Outcome Measure
Part 1 & 2: Changes in pERK levels
Measure Description
Evaluates the intended mechanism of action (MoA) modulation of KRAS inhibition and target engagement effect of PF-07934040 in peripheral blood of participants with advanced solid tumor malignancies.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days)
Outcome Measure
Part 1: Objective Response - Number of Participants With Objective Response
Measure Description
Percentage of participants with objective response-based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by the Investigator including overall response rate (ORR), progression free survival (PFS), and overall survival (OS).
Time Frame
Baseline and every 8 to 12 weeks through time of confirmed disease progression, death, unacceptable toxicity, or through study completion, approximately 2 years
Outcome Measure
Part 1: Effect of Food on Cmax
Measure Description
Evaluate the effect of food on Cmax of PF-07934040 as monotherapy.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days)
Outcome Measure
Part 1: Effect of Food on Tmax
Measure Description
Evaluate the effect of food on Tmax of PF-07934040 as monotherapy.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days)
Outcome Measure
Part 1: Effect of Food on AUClast
Measure Description
Evaluate the effect of food on AUClast of PF-07934040 as monotherapy.
Time Frame
Baseline through end of Cycle 1 (All cycles are 28 days)
