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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Pfizer
- 入组人数
- 64
- 试验地点
- 53
- 主要终点
- Part 1 & 2: Incidence of Adverse Events (AEs)
研究概览
简要总结
The purpose of this study is to learn about the safety and effects of the study medicine alone or when given together with other anti-cancer therapies. This study also aims to find the best dose.
This study is seeking participants who have solid tumors (a mass of abnormal cells that forms a lump or growth in the body) that:
- are advanced (cancer that doesn't disappear or stay away with treatment) and
- have a KRAS gene mutation (a change in the DNA of the KRAS gene that can cause cells to grow in very high numbers).
This includes (but limited to) the following cancer types:
Non-Small Cell Lung Cancer (NSCLC): It's a type of lung cancer where the cells grow slowly but often spread to other parts of the body.
Colorectal Cancer (CRC): This is a disease where cells in the colon (a part of large intestine) or rectum grow out of control.
Pancreatic ductal adenocarcinoma (PDAC): This is a cancer that starts in the ducts of the pancreas but can spread quickly to other parts of the body. Pancreas is a long, flat gland that lies in the abdomen behind the stomach. Pancreas creates enzymes that help with digestion. It also makes hormones that can help control your blood sugar levels.
All participants in this study will take the study medication (PF-07934040) as pill by mouth twice a day repeating for 21-day or 28-day cycles.
Depending on which part of the study participants are enrolled into they will receive the study medication (PF-07934040 alone or in combination with other anti-cancer medications). These anti-cancer medications will be given in the study clinic by intravenous (IV) that is directly injected into the veins at various times (depending on the treatment) during the 21-day or 28-day cycle.
Participants can continue to take the study medication (PF-07934040) and the combination anti-cancer therapy until their cancer is no longer responding.
The study will look at the experiences of people receiving the study medicines. This will help see if the study medicines are safe and effective.
Participants will be involved in this study for up to 4 years. During this time, they will come into the clinic between 1 to 4 times in each 21-day or 28-day cycle. After they have stopped taking the study medication (at about at 2 years) they will be followed for another two years to see how they are doing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •PDAC, CRC, Other tumor types: Confirmed KRAS mutation, any variant
- •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.
- •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.
- •NSCLC (2-3L): Participants must have received prior lines of anti-cancer treatment and progressed on at least a platinum-containing chemotherapy regimen or ICI. Participants may have had only one or two prior lines of therapy in the advanced/metastatic setting. For participants with EGFR, ALK, or other genomic tumor alterations, participants must have progressed on approved therapy for these alterations.
- •CRC (2-3L): Participants must have had one or two prior lines of therapy for mCRC. For either one or two prior treatments, these regimens must have included a fluoropyrimidine, oxaliplatin, and/or irinotecan for one prior treatment, exposure to VEGF/VEGF receptor (VEGFR) inhibitor is optional;
- •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.
- •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. If relapse occurred within 6 months of last dose of adjuvant treatment or neoadjuvant therapy, the participant would be considered 2L, and not 1L.
- •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.
- •CRC (1L) Cohort B3/B4: Participants must not have received prior therapy for metastatic disease and not be a candidate for other targeted therapy or immunotherapy. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy. If relapse occurred within 6 months of last dose of adjuvant or neoadjuvant therapy, then the participant would be considered 2L, and not 1L.
- •NSCLC (1L) Cohort C2: Participants must have a TPS ≥50% and must not have received prior systemic treatment setting.
- •NSCLC (1L) Cohort C3: Participants with any TPS and must not have received prior systemic treatment setting.
排除标准
- •Active or history of pneumonitis/ILD or pulmonary fibrosis requiring treatment with systemic steroid therapy.
- •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 abnormalities.
研究组 & 干预措施
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
干预措施: pemetrexed (Combination Product)
Part 2a Cohort A1
Monotherapy dose expansion in 2-3L PDAC. PF-07934040 at prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2a Cohort D1
Monotherapy dose expansion in Other Indications. PF-07934040 at prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort B4
Combination (PF-07934040 + FOLFOX + Cetuximab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort B4
Combination (PF-07934040 + FOLFOX + Cetuximab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Fluorouracil (Combination Product)
Part 2a Cohort B1
Monotherapy dose expansion in 2-3L CRC. PF-07934040 at prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 1
PF-07934040 Monotherapy Dose Escalation PF-07934040 monotherapy at prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort A2
Combination (PF-07934040 + Gemcitabine + Nab-paclitaxel) dose escalation/expansion in 1L PDAC.
Prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2a Cohort C1
Monotherapy dose expansion in 2-3L NSCLC. PF-07934040 at prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort A2
Combination (PF-07934040 + Gemcitabine + Nab-paclitaxel) dose escalation/expansion in 1L PDAC.
Prescribed dose and frequency in 28-day cycles
干预措施: Gemcitabine (Combination Product)
Part 2b Cohort B2
Combination (PF-07934040 + Cetuximab) dose escalation/expansion in 2-3L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: PF-07934040 (Drug)
Part 2b Cohort B2
Combination (PF-07934040 + Cetuximab) dose escalation/expansion in 2-3L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Cetuximab (Combination Product)
Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Bevacizumab (Combination Product)
Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Leucovorin (Combination Product)
Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Oxaliplatin (Combination Product)
Part 2b Cohort A2
Combination (PF-07934040 + Gemcitabine + Nab-paclitaxel) dose escalation/expansion in 1L PDAC.
Prescribed dose and frequency in 28-day cycles
干预措施: Nab-paclitaxel (Combination Product)
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
干预措施: Carboplatin (Combination Product)
Part 2b Cohort C2
Combination (PF-07934040 + Pembro or Sasanlimab) dose escalation/expansion in 1L NSCLC (TPS ≥ 50%)
Prescribed dose and frequency in 21-day cycles (for pembro) or 28-day cycles (for sasanlimab)
干预措施: Pembrolizumab (Combination Product)
Part 2b Cohort B4
Combination (PF-07934040 + FOLFOX + Cetuximab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Cetuximab (Combination Product)
Part 2b Cohort B3
Combination (PF-07934040 + FOLFOX + Bevacizumab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Fluorouracil (Combination Product)
Part 2b Cohort C2
Combination (PF-07934040 + Pembro or Sasanlimab) dose escalation/expansion in 1L NSCLC (TPS ≥ 50%)
Prescribed dose and frequency in 21-day cycles (for pembro) or 28-day cycles (for sasanlimab)
干预措施: Sasanlimab (Combination Product)
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
干预措施: PF-07934040 (Drug)
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
干预措施: Paclitaxel (Combination Product)
Part 2b Cohort B4
Combination (PF-07934040 + FOLFOX + Cetuximab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Oxaliplatin (Combination Product)
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
干预措施: Cisplatin (Combination Product)
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
干预措施: Pembrolizumab (Combination Product)
Part 2b Cohort B4
Combination (PF-07934040 + FOLFOX + Cetuximab) dose escalation/expansion in 1L CRC
Prescribed dose and frequency in 28-day cycles
干预措施: Leucovorin (Combination Product)
Part 2b Cohort C2
Combination (PF-07934040 + Pembro or Sasanlimab) dose escalation/expansion in 1L NSCLC (TPS ≥ 50%)
Prescribed dose and frequency in 21-day cycles (for pembro) or 28-day cycles (for sasanlimab)
干预措施: PF-07934040 (Drug)
结局指标
主要结局
Part 1 & 2: Incidence of Adverse Events (AEs)
时间窗: Start of treatment up to 30 days after last dose or start of new anticancer therapy (whichever occurs first)
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.
PART 1 & 2: Number of participants with laboratory abnormalities
时间窗: From start of treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first
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).
Part 1: Number of participants with Dose-limiting toxicities (DLT)
时间窗: Baseline up to 28 days
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
Part 2: Objective Response - Number of Participants With Objective Response (alone or in combination)
时间窗: Baseline and every 8 to 12 weeks through time of confirmed disease progression, death, unacceptable toxicity, or through study completion, approximately 2 years'
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.
次要结局
- Part 1& 2: Time to Reach Maximum Observed Serum Concentration (Tmax)(Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days))
- Part 1: Effect of Food on AUClast(Baseline through end of Cycle 1 (All cycles are 28 days))
- Part 1: Effect of Food on Tmax(Baseline through end of Cycle 1 (All cycles are 28 days))
- Part 1 & 2: Changes in pERK levels(Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days))
- Part 1: Objective Response - Number of Participants With Objective Response(Baseline and every 8 to 12 weeks through time of confirmed disease progression, death, unacceptable toxicity, or through study completion, approximately 2 years)
- Part 1: Effect of Food on Cmax(Baseline through end of Cycle 1 (All cycles are 28 days))
- Part 1 & 2: Maximum Observed Serum Concentration (Cmax)(baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days))
- Part 1 & 2: Serum Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Baseline through end of Cycle 1 (All cycles are 28 days except part 2b Cohort C2 which are 21 days))