A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF 06952229 IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 49
- 试验地点
- 15
- 主要终点
- Number of Participants With First-Cycle Dose-Limiting Toxicitys (DLTs) by Treatment
研究概览
简要总结
A Phase 1 dose escalation and expansion study evaluating safety, tolerability and pharmacokinetics of PF-06952229 in adult patients with advanced solid tumors.
详细描述
This is a Phase 1, open label, multi center, multiple dose, dose escalation and expansion, safety, tolerability, PK, and pharmacodynamics study of PF 06952229 in previously treated patients with advanced or metastatic cancers that may have high TGFbeta signatures and EMT expression.
The study includes Parts 1A and 1B, which are dose-escalation for monotherapy and combination therapy with enzalutamide, respectively, and Parts 2A and 2B, which are dose expansion for monotherapy and combination therapy with enzalutamide, respectively.
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
- •For Part 1A: Histological or cytological diagnosis of a solid tumor that is advanced/metastatic, patients are intolerant to standard treatment, resistant to standard therapy or for which no standard therapy is available for the following tumor types:
- •Breast cancer; Prostate cancer (mCRPC testosterone less than 50 ng/dL); Squamous cell cancer of the head and neck; Melanoma; Mesothelioma; Pancreatic cancer; Colorectal cancer; Renal cell carcinoma; Hepatocellular cancer.
- •For Part 1B:
- •histological or cytological diagnosis of mCRPC 3 Part 2A and Part 2B:
- •Histologically or cytologically confirmed prostate adenocarcinoma metastatic disease.
- •Effective castration with serum testosterone levels 0.5 ng/mL (1.7 nmol/L).
- •Having received 3 or more cycles of prior docetaxel therapy (before or after abiraterone).
- •Having PD while receiving abiraterone acetate within 12 months of abiraterone treatment initiation.
- •Progressive disease (PD) by:
- •Progression in measurable disease per RECIST 1.1 criteria. Patient with measurable disease must have at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be at least 10 mm when measured by computed tomography (CT) (CT scan thickness no greater than 5 mm) or magnetic resonance imaging (MRI). Lymph nodes should be greater than or equal to 15 mm in short axis. As defined by PCWG2, if lymph node metastasis is the only evidence of metastasis, it must be greater than or equal to 20 mm in diameter when measured by spiral CT or MRI. Previously irradiated lesions, primary prostate lesion, and bone lesions will be considered non-measurable disease, or
- •Appearance of 2 or more new bone lesions (PCWG2). They must be confirmed by other imaging modalities (CT; MRI) if ambiguous results, or
- •Rising PSA defined (PCWG2) as at least 2 consecutive rises in PSA to be documented over a reference value (measure 1) taken at least 1 week apart. • Prior abiraterone acetate must be stopped at least 2 weeks before study treatment.
- •Patients must have recently obtained archival tumor tissue available for submission to the sponsor (except for Part 2A - monotherapy dose expansion). Patients enrolled in Part 1 and Part 2 should have access to their archival formalin-fixed paraffin-embedded material, collected within 6 months of screening, containing tumor that is of diagnostic quality and representative of their diagnosed malignancy or whenever possible, consent to undergo a biopsy during screening. The sponsor should be contacted if obtaining a new biopsy is not medically feasible for approval to enroll, prior to initiating screening activities.
- •Patients entering the study in the subgroup(s) requiring mandatory pre- and on treatment tumor biopsies in Part 2A and 2B must have a tumor amenable to biopsy and consent to these planned biopsy procedures. The sponsor should be contacted if obtaining a pre-treatment and on treatment biopsies is not medically feasible for approval to enroll, prior to initiating screening activities.
- •Age 18 years or older
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or
- •Adequate bone marrow function (see Appendix 3), including:
- •Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mm3;
- •Platelets greater than or equal to 100,000/mm3;
- •Hemoglobin greater than or equal to 9 g/dL.
- •Adequate renal function, including serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) or estimated creatinine clearance greater than or equal to 60 mL/min as calculated using the method standard for the institution. In equivocal cases, a 24 hour urine collection test can be used to estimate the creatinine clearance more accurately. In Part 2: Serum creatinine of less than or equal to 3.0 x upper limit of normal.
- •Adequate liver function, including:
- •Total serum bilirubin less than or equal to 0.5 x ULN unless the patient has documented Gilbert syndrome;
- •Aspartate and alanine aminotransferase (AST and ALT) less than or equal to 2.5 x ULN less than or equal to 5.0 x ULN if there is liver involvement by the tumor;
- •Alkaline phosphatase less than or equal 2.5 x ULN less than or equal to 5 x ULN in case of bone metastasis).
- •Serum phosphate within normal range (if abnormal, must be nonclinically significant per the Investigator and approval for patient inclusion after agreement from sponsor.
- •Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 except for alopecia and those listed in the specific exclusion criteria.
- •For Part 1A monotherapy dose escalation: serum pregnancy test (for females of childbearing potential) negative at screening.
- •For Part 1A monotherapy dose escalation: female patients of nonchildbearing potential must meet at least 1 of the following criteria:
- •Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and must have a serum follicle stimulating hormone level confirming the postmenopausal state;
- •Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- •Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
- •Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
- •Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
- •Exclusion Criteria
- •Patients with any of the characteristics/conditions listed below will not be included in the study:
- •Any labs may be repeated for confirmation. Only the lab result requiring confirmation must be repeated, not the entire panel.
- •For Parts 1B current or prior treatment with enzalutamide within 24 days prior to first dose
- •For 2A, and 2B:
- •Prior chemotherapy other than docetaxel for prostate cancer, except estramustine, adjuvant/neoadjuvant treatment completed more than 3 years ago;
- •Less than 28 days elapsed from prior treatment with chemotherapy, immunotherapy, radiotherapy, or surgery to the time of study enrollment.
- •Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by baseline brain MRI (or CT with contrast if MRI is medically contraindicated), clinical symptoms, cerebral edema, and/or progressive growth. If contrast is medically contraindicated, a non-contrast CT scan may be performed.
- •Patients with a history of CNS metastases or cord compression.
- •Liver metastases at baseline as evidenced by CT scan or MRI that may be at risk for bleeding, such as those that are greater than 1 cm,
- •Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of life threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement). Note: Patients with indwelling catheter for drainage, or requirement for drainage no more frequently than monthly will be allowed.
- •Any other active malignancy within 3 years prior to study entry, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
- •Patients with a history of clinically significant tumor bleeding (except for bleeding in a post-operative setting), coagulopathy or arterio-venous malformations (AVM) or aneurysms in the CNS, liver, lung or other major organ of the body. Patients with known Osler-Weber-Rendu disease, Hemophilia A, Hemophilia B (Christmas Disease), Von Willibrand's Disease, Factor 13 deficiency and Factor 7 deficiency, antibodies to Factors 8 and 7, history of other bleeding diatheses and abnormal INR values.
- •Evidence of a tumor that compresses or invades major blood vessels or tumor cavitation that in the opinion of the investigator is likely to bleed.
- •Major surgery within 4 weeks prior to first dose.
- •Prior organ transplantation including heart and allogeneic stem cell transplantation.
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排除标准
- 未提供
研究组 & 干预措施
Prostate Cancer Dose Level 4 (Part 1B)
PF-06952229 at 750 mg BID in combination with enzalutamide
干预措施: PF-06952229 (Drug)
Dose Level 1 (Part 1A)
PF-06952229 at 20mg twice daily (BID)
干预措施: PF-06952229 (Drug)
Dose Level 2 (Part 1A)
PF-06952229 at 40 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 5 (Part 1A)
PF-06952229 at 250 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 3 (Part 1A)
PF-06952229 at 80 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 4 (Part 1A)
PF-06952229 at 150 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 6 (Part 1A)
PF-06952229 at 375 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 7 (Part 1A)
PF-06952229 at 500 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 8 (Part 1A)
PF-06952229 at 625 mg BID
干预措施: PF-06952229 (Drug)
Dose Level 9 (Part 1A)
PF-06952229 at 750 mg BID
干预措施: PF-06952229 (Drug)
Prostate Cancer Dose Level 1 (Part 1B)
PF-06952229 at 375 mg BID in combination with enzalutamide
干预措施: PF-06952229 (Drug)
Prostate Cancer Dose Level 1 (Part 1B)
PF-06952229 at 375 mg BID in combination with enzalutamide
干预措施: Enzalutamide (Drug)
Prostate Cancer Dose Level 3 (Part 1B)
PF-06952229 at 625 mg BID in combination with enzalutamide
干预措施: Enzalutamide (Drug)
Prostate Cancer Dose Level 2 (Part 1B)
PF-06952229 at 500 mg BID in combination with enzalutamide
干预措施: PF-06952229 (Drug)
Prostate Cancer Dose Level 2 (Part 1B)
PF-06952229 at 500 mg BID in combination with enzalutamide
干预措施: Enzalutamide (Drug)
Prostate Cancer Dose Level 3 (Part 1B)
PF-06952229 at 625 mg BID in combination with enzalutamide
干预措施: PF-06952229 (Drug)
Prostate Cancer Dose Level 4 (Part 1B)
PF-06952229 at 750 mg BID in combination with enzalutamide
干预措施: Enzalutamide (Drug)
Prostate Cancer (Part 2A)
PF-06952229 at recommended Phase 2 Dose BID
干预措施: PF-06952229 (Drug)
Prostate Cancer (Part 2B)
PF-06952229 at recommended phase 2 dose BID in combination with enzalutamide
干预措施: PF-06952229 (Drug)
Prostate Cancer (Part 2B)
PF-06952229 at recommended phase 2 dose BID in combination with enzalutamide
干预措施: Enzalutamide (Drug)
结局指标
主要结局
Number of Participants With First-Cycle Dose-Limiting Toxicitys (DLTs) by Treatment
时间窗: Within 28 days of first dose or until the participant completed the first cycle of therapy if there were treatment delayed (on average 28 days).
First cycle DLTs were utilized to determine the max tolerated dose and future escalations or deescalations. Any of the following adverse events occurred in the first cycle of treatment which were clinically significant were classified as DLTs: Hematologic: Thrombocytopenia Grade 4 for \>=7 days, or Grade 3 or 4 associated with \>= Grade 2 clinically significant bleeding or requiring platelet transfusion; Neutropenia Grade 4 for \>=7 days; Grade\>=3 neutropenia with infection; Anemia Grade 4 or Grade 3 requiring blood transfusion. Nonhematologic: Grade\>=3 toxicities that were considered clinically significant; Alanine aminotransferase/aspartate aminotransferase\>3x the upper limit of normal (ULN) with bilirubin\>2x ULN without another explanation; Grade 3 nausea, vomiting or diarrhea that did not resolve within 4 days despite maximal supportive therapy. Nonhematologic and Non-Hepatic: Any toxicity caused\>= 2 weeks of dose delay or preventing participants from receiving 75% of study drug.
Number of Participants With Treatment-Emergent Adverse Events (Treatment Related)
时间窗: Baseline up to 28 days after last dose of study treatment ( up to approximately 2 years)
Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
时间窗: Baseline up to 28 days after last dose of study treatment ( up to approximately 2 years)
Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test \[for all female participants\]) and urine (urine pregnancy test \[for all female participants\]). Clinical significance of laboratory parameters was determined at the investigator's discretion.
次要结局
- Maximum Observed Plasma Concentration (Cmax) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Maximum Observed Plasma Concentration (Cmax) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Time of Observed Maximum Plasma Concentration (Tmax) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Time of Observed Maximum Plasma Concentration (Tmax) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Apparent Clearance (CL/F) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 21 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Apparent Volume of Distribution (Vz/F) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Apparent Clearance (CL/F) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Apparent Volume of Distribution (Vz/F) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Terminal Elimination Half-Life (T1/2) of PF-06952229 (Part 1A)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 and 7 of cycle 1, 0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 2.)
- Terminal Elimination Half-Life (T1/2) of PF-06952229 (Part 1B)(0 (pre dose), 0.5, 1, 2, 4, 6 and 12 hours (post dose) on Day 1 of cycle 1 and cycle 2)
- Number of Participants With Prostate Specific Antigen 50 (PSA50) Response(Baseline, Cycle 1 Day 1 (at the beginning of Cycle 1), and then every 3 cycles (each cycle is 28 days) until end of treatment (an average of 1 year))
- Percentage of Participants With Objective Response(Baseline and every 8 to 12 weeks through time of confirmed disease progression, unacceptable toxicity, or through study completion, approximately 2 years.)