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PHASE 1/2A DOSE ESCALATION AND EXPANSION STUDY EVALUATING SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMICS AND ANTI-TUMOR ACTIVITY OF PF-06873600 AS A SINGLE AGENT AND IN COMBINATION WITH ENDOCRINE THERAPY

A Study of PF-06873600 in People With Cancer

153

Of 151 participants in the safety analysis set, all participants were female, with the majority were White (71.5%). The median age was 59.0 years (range: 28, 84), and the median weight was 70.4 kg (range: 42.5, 134.0). A total of 81 (53.6%) participants had baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 69 (45.7%) baseline ECOG PS 1, and 1 (0.7%) baseline ECOG PS as 2. Of 151 participants in the safety analysis set in this study, 144 (95.4%) had the diagnosis of breast cancer and (136 [90.1%]) were hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-); 5 (3.3%) participants had triple negative breast cancer (TNBC). Seven (4.6%) had the diagnosis of ovarian cancer. Cohorts 1B, 2A and 2C included advanced or metastatic breast cancer (mBC) participants only.

A total of 153 participants were assigned to treatment and 151 (98.7%) were treated in the study. In Part 1A, a total of 53 participants were assigned to treatment and 51 were treated. In Part 1B, a total of 16 participants were assigned to treatment and treated. In Part 1C, a total of 11 participants were assigned to treatment and treated. A total of 45 and 28 participants were assigned to treatment and treated in Part 2A and Part 2C, respectively. The median duration of PF-06873600 treatment was 58.0 days (range: 5, 1093) in Part 1A; a median of 2.0 cycles (range: 1, 36) were administered. The median duration of PF-06873600 treatment was 125.5 days (range: 11, 419) in Part 1B; a median of 5.0 cycles (range: 1, 15) were administered. The median duration of PF-06873600 treatment was 112.0 days (range: 25, 466) in Part 1C; a median of 4.0 cycles (range: 1, 16) were administered. The median duration of PF-06873600 treatment was 120.0 days (range: 18, 636) in Part 2A; a median of 5.0 cycles (range: 1, 23) were administered. The median duration of PF-06873600 treatment was 148.5 days (range: 1, 413) in Part 2C; a median of 5.5 cycles (range: 1, 15) were administered.

Because the frequency of certain medical events may be underestimated by reliance on a single Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT), certain PTs representing a similar medical event were analyzed in aggregate using Customized Query (CQ) and represented throughout this report. Of the 1385 all-causality treatment-emergent adverse events (TEAEs) reported in 147 (97.4%) participants across all cohorts, 832 events reported in 138 (91.4%) participants were considered to be treatment-related. The most frequently reported all-causality TEAEs (>=30% of participants) were nausea (62.9%), anaemia (CQ including anaemia, haemoglobin decreased, red blood cell count decreased, haematocrit decreased, normochromic anaemia, normocytic anaemia and normochromic normocytic anaemia) (44.4%), fatigue (CQ including asthenia, fatigue, tiredness and malaise) (43.7%), neutropenia (CQ including neutropenia, neutrophil count decreased, neutrophil percentage decreased, cyclic neutropenia, agranulocytosis, granulocytopenia and granulocyte count decreased) (37.7%), and vomiting (35.8%). The most frequently reported treatment-related TEAEs (>=20% of participants) were nausea (60.9%), anaemia (CQ) (41.1%), fatigue (CQ) (39.7%), neutropenia (CQ) (37.1%), vomiting (33.8%), alopecia (27.8%), leukopenia (CQ including leukopenia and white blood cell count decreased) (24.5%), and headache (21.2%). A total of 34 (22.5%) participants had all-causality serious adverse events (SAEs) reported. The most frequently reported all-causality SAEs were febrile neutropenia (5 [3.3%] participants), abdominal pain, colitis, and hypotension (each in 3 [2.0%] participants). A total of 13 (8.6%) participants had treatment-related SAEs reported. The most frequently reported treatment-related SAEs were febrile neutropenia (5 [3.3%] participants) followed by neutropenia (CQ), colitis, and stomatitis (each in 2 [1.3%] participants). A total of 69 (45.7%) participants had maximum Grade 3-4 all-causality TEAEs, and 54 (35.8%) participants had maximum Grade 3-4 treatment-related TEAEs. A total of 19 (12.6%) deaths reported as of primary completion date (PCD). Five (3.3%) deaths were reported on treatment (while receiving study treatment or within 28 days after last dose of study treatment or start of new anti-cancer therapy minus 1 day, whichever occurred first). Grade 5 TEAE of cardiac arrest was reported in 2 (1.3%) participants; Grade 5 TEAEs of death, disease progression, gastrointestinal bacterial infection, haemolysis, and respiratory failure were each reported in 1 (0.7%) participant. A total of 2 (1.3%) participants reported treatment-related Grade 5 TEAEs. Grade 5 treatment-related TEAEs of cardiac arrest and gastrointestinal bacterial infection were each reported in 1 (0.7%) participant. Dose-Limiting Toxicity (DLT): In Part 1A, a total of 6 (9.4%) participants had DLTs reported. Two participants in PF-06873600 35 mg BID cohort had DLTs: * One participant had Grade 4 neutrophil count decreased, considered treatment-related. * One participant had Grade 4 neutrophil count decreased and Grade 4 platelet count decreased, both AEs considered treatment-related. Four participants in PF-06873600 50 mg BID cohort had DLTs: * One participant had Grade 4 febrile neutropenia, considered treatment-related. * One participant had Grade 3 fatigue, considered treatment-related. * One participant had Grade 4 febrile neutropenia, Grade 4 thrombocytopenia, Grade 5 cardiac arrest, and Grade 4 multiple organ dysfunction syndrome, all considered treatment-related. * One participant had Grade 3 febrile neutropenia and Grade 3 colitis, both AEs considered treatment-related.

Primary Efficacy Endpoint - Objective Response Rate (ORR) in Part 2: A total of 67 participants were evaluable for objective response (OR) in Part 2. A total of 8 (11.9%) participants achieved partial response (PR). In Part 2A (PF-06873600+fulvestrant [Ful], HR+/HER2- mBC post CDK4/6i), 3 participants achieved OR (all PRs); the ORR was 6.7% (95% confidence interval [CI]: 1.4%, 18.3%). In Part 2C (PF-06873600+Ful, HR+/HER2- mBC CDK4/6i naive/post endocrine therapy [ET]), 5 participants achieved OR (all PRs); the ORR was 22.7% (95% CI: 7.8%, 45.4%). Secondary Efficacy Endpoints - Duration of Response (DoR): The DoR for 1 confirmed responder in Part 2C was 5.8 months. The other 7 confirmed responders were censored: 1 participant in Part 2A for start of new anti-cancer therapy, 3 participants (2 in Part 2A and 1 in Part 2C) due to study being terminated by sponsor, and 3 participants in Part 2C for being event free as of the cutoff date. Secondary Efficacy Endpoints - Progression Free Survival (PFS): In Part 2A (PF-06873600+Ful, HR+/HER2- mBC post CDK4/6i), among 45 participants in full analysis set, 27 had an event of disease progression. The estimated median PFS was 5.6 months (95% CI: 3.9, 7.8). In Part 2C (PF-06873600+Ful, HR+/HER2- mBC CDK4/6i naive), among 28 participants in full analysis set, 8 had an event of disease progression or death. The estimated median PFS was 11.1 months (95% CI: 7.5, not evaluable). Secondary Efficacy Endpoints - ORR in Part 1: In Part 1A, 1 participant achieved PR, treated at PF-06873600 IR 50 mg BID dose level. In Part 1B, 1 participant achieved PR, treated with PF-06873600 IR 25 mg BID plus fulvestrant combination. In Part 1C, 1 participant achieved PR, treated with PF-06873600 IR 25 mg BID after two 20 mg MR lead-in doses. Pharmacokinetic (PK) Results: Following oral administration of the IR formulation, PF-06873600 was rapidly absorbed, with median Tmax values of 1 to 4 hours after the first dose. The geometric mean PK parameters of PF-06873600, including Cmax, Cmin, and AUC, in general, increased with dose up to at least 35 mg BID. There was minimal accumulation following repeated BID dosing, with geometric mean accumulation ratio (Rac) ranging from 0.7 to 1.3. The arithmetic mean t1/2 ranged from 2 to 3 hours. PF-06873600 exposure exhibited moderate to high inter-participant variability. At 25 mg BID, the geometric mean coefficient of variation percentage (CV%) values were 58% and 56% for single dose AUCinf and Cmax, respectively. After multiple dosing at 25 mg BID, the geometric mean CV% values were 45%, 43% and 119% for AUCtau, Cmax and Cmin, respectively. The plasma exposures of PF-06873600 were largely comparable between monotherapy and combination therapy with fulvestrant or letrozole. Pharmacodynamic Results: Following PF-06873600 IR 25 mg BID monotherapy in Part 1A, the median change in Ki67 positive cells was -11.67%, and the median change in phospho-retinoblastoma (pRb) H-score was -16.49. Following PF-06873600 IR 25 mg BID / fulvestrant combination treatment in Part 1B and Part 2A, the median change in Ki67 positive cells was -35.90%, and the median change in pRb H-score was -31.88.

Based on Part 1 data, IR 25m g BID was chosen as the recommended dose for monotherapy and ET combination. PF-06873600 demonstrated modest anti-tumor activity as monotherapy. In Part 2 (dose expansion cohorts), PF-06873600 demonstrated early signs of efficacy in combination with Ful. Altough PF-06873600 showed overall favorable benefit risk profile consistent with CDK4/6 inhibitors, the data do not support the profile needed to justify further clinical development. This study was terminated by Sponsor.

Nov. 13, 2024

Yes

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230326

Kawai Norisuke

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Complete

Sept. 29, 2021

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

* Have a diagnosis of Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) breast cancer (prior combined CDK 4/6 inhibitor and endocrine therapy and 1 or 2 prior lines of chemotherapy)
* Have a diagnosis of metastatic triple negative breast cancer (TNBC) (up to 1-2 prior lines of chemotherapy)
* Have a diagnosis of advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC) (up to 2-3 prior lines of therapy)
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Measurable disease or non-measurable disease and refractory to or intolerant of existing therapies (Part 1)
* Measurable disease as defined by RECIST 1.1 is required (Part 1B and Part 2 only)

* Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases
* Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
* Major surgery or radiation within 4 weeks prior to study entry
* Last anti-cancer treatment within 2 weeks prior to study entry
* Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
* Pregnant or breastfeeding female patients
* Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastro intestinal function or GI disease

Both

Advanced solid tumor

* Single Agent Dose Escalation: PF-06873600 tablet for oral dosing
* Part 1B: PF-06873600 tablet for oral dosing and Endocrine Therapy 1
* Part 1B: PF-06873600 tablet for oral dosing and Endocrine Therapy 2
* Dose Expansion Arm A: PF-06873600 tablet for oral dosing as a Single Agent
* Dose Expansion Arm B: PF-06873600 tablet for oral dosing as a Single Agent
* Dose Expansion Arm C: PF-06873600 tablet for oral dosing and Endocrine Therapy 1
* Dose Expansion Arm D: PF-06873600 tablet for oral dosing and Endocrine Therapy 1
* Dose Expansion Arm E: PF-06873600 tablet for oral dosing and Endocrine Therapy 2

* Number of patients with dose limiting toxicities in the Dose Escalation portion
* Safety and Tolerability as assessed by adverse event, safety laboratory abnormalities (hematology, chemistry, coagulation and urinalysis), vital signs and heart rate corrected QT interval)
* Objective Response Rate (ORR) observed in patients in the Dose Expansion Arms

* PK parameter of PF-06873600
* ORR per RECIST version 1.1
* Time-to-event endpoint
* PD biomarkers (pRb and Ki67) in tumor tissue

Sept. 06, 2021

Bulgaria/Canada/Russian Federation/Ukraine/United States