PF-06671008 Dose Escalation Study in Advanced Solid Tumors

Study Overview
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Brief Summary
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The study will evaluate the safety, pharmacokinetics and pharmacodynamics of increasing doses of PF-06671008 in patients with advanced solid tumors with the potential to have P-cadherin expression. The study will then expand to look at the selected dose in patients with P-cadherin expressing TNBC, CRC or NSCLC.

Official Title
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A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06671008 IN PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: PF-06671008
* Drug: PF-06671008


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Diagnosis of tumor type with the potential to have P-cadherin expression that is resistant to standard therapy or for which no standard therapy is available Performance status of 0 or 1 Adequate bone marrow, kidney and liver function Key Exclusion Criteria Known CNS disease including, but not limited to, metastases Current or history of seizure disorder History of or active autoimmune disorders Active bacterial, fungal or viral infection Major surgery, anti-cancer therapy, or radiation therapy within 4 weeks of study treatment Requirement for systemic immune suppressive medication Grade 2 or greater peripheral neuropathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06671008<br> | Drug: PF-06671008<br>* Dose Escalation Phase - Part 1<br>Drug: PF-06671008<br>* Dose Expansion Phase - Part 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) - Part 1 | DLT was defined as any of the following adverse events occurring in the first cycle of treatment (21 days after the first dose): a) Hematologic: Febrile neutropenia defined as an absolute neutrophil count (ANC) <1.0 x 10^9/L with a single temperature of >38.3°C, or 101°F, or a sustained temperature of >=38°C, or 100.4°F, for more than one hour; b) Non-hematologic: Delay by more than 2 weeks in receiving the next scheduled dose due to persisting treatment related toxicities; c) Any grade 3 or 4 clinically-relevant hematologic or non-hematologic toxicity. | Baseline through Day 21 (Cycle 1) | 
| Number of Participants With Objective Response (OR) - Part 2 | Number of participants with OR based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration (Cmax) of PF-06671008 | Maximum serum concentration (Cmax) of PF-06671008 was observed directly from data. Geometric mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) of PF-06671008 | Time for Maximum serum concentration (Tmax) of PF-06671008 was observed directly from data as time of first occurrence. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Terminal Elimination Half-life (t1/2) of PF-06671008 | Terminal elimination half-life (t1/2) of PF-06671008 was calculated as ln(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. Arithmetic mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06671008 | Tau refers to the dosing interval, which was 1 week. Area under the concentration-time profile from time 0 to time tau (AUCtau) was determined using linear/log trapezoidal method. Geometric mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Area Under the Curve From Time 0 Extrapolated to Infinity Time (AUCinf) of PF-06671008 | AUCinf was calculated as AUClast +(Clast*/kel), where AUClast is area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* is the predicted serum concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. Geometric mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Systemic Clearance (CL) of PF-06671008 | Systemic Clearance (CL) was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to IV arms. Geometric mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Apparent Clearance (CL/F) of PF-06671008 | Apparent Clearance (CL/F) was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to SC arm. Geometric mean was not calculated if fewer than 3 participants had reportable parameter values. | C1D1 0, 1, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose, C2D1 0, 2, 4, 8, 24, 48, 72 and 96 hrs post-dose | 
| Number of Participants With OR - Part 1 | Number of participants with OR based on assessment of CR or PR according to RECIST v1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline and every 6 weeks for the first 6 months, then every 12 weeks until disease progression, unacceptable toxicity, or up to 24 months | 
| Number of Participants With Progression Free Survival (PFS) - Part 2 | The period from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was Death). | Baseline and every 6 weeks for the first 6 months, then every 12 weeks until disease progression or unacceptable toxicity, or up to 24 months | 
| Number of Participants With Overall Survival (OS) - Part 2 | The period from the start of study treatment to date of death due to any cause. OS was calculated as (the death date minus the date of first dose of study medication plus 1) divided by 7. Death was determined from AE data (where outcome was death) or from follow-up contact data (where the participant current status was death). | Baseline and every 6 weeks for the first 6 months, then every 12 weeks until disease progression or unacceptable toxicity, or up to 24 months | 
| Number of Participants With Anti Drug Antibodies (ADA) and Neutralizing Antibodies (NAb) Against PF-06671008 | ADA against PF-06671008 in human serum samples was determined following a tiered approach using screening, confirmation, and titer/quantification by semi-quantitative enzyme linked immunosorbent assay (ELISA). Endpoint titer >=1.18 was considered positive. | C1D1 0 hrs, D15 0 hrs, and C2D1 0 hrs, and D1 0 hrs post additional dosings, up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P-cadherin, PF-06671008, solid tumors, lung cancer, breast cancer, colorectal cancer, NSCLC, TNBC, CRC, neoplasms, Triple negative breast cancer, Non-small cell lung cancer