Charles Zacharchuk

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy

BACKGROUNDnThis phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer.nnnPATIENTS AND METHODSnPatients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers.nnnRESULTSnSeventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen.nnnCONCLUSIONSnBosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.BACKGROUNDnThis phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer.nnnPATIENTS AND METHODSnPatients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers.nnnRESULTSnSeventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen.nnnCONCLUSIONSnBosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas). Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens. Clin Cancer Res; 18(4); 1092–100. ©2011 AACR.

Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy

The central role played by the class IA phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with “PI3K activated” tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize “PI3K activated” tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into “pathway on” and “pathway off” subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific “pathway on” patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.

A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF‐05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327‐01)

AIMSnThe pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed.nnnMETHODSnIn this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6u2009mgu2009kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria.nnnRESULTSnBaseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term pyrexia was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA).nnnCONCLUSIONSnThis study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.

Biosimilars for the Treatment of Cancer: A Systematic Review of Published Evidence

BackgroundBiologic treatments for cancer continue to place a significant economic burden on healthcare stakeholders. Biosimilar therapies may help reduce this burden through cost savings, thereby increasing patient access.ObjectivesThe purpose of this study was to collate all published data to assess the weight of available evidence (quantity and quality) for proposed monoclonal antibody biosimilars and intended copies, for the treatment of cancer.MethodsMEDLINE®, Embase®, and ISI Web of Science® databases were searched to September 2015. Conference proceedings (17) were searched (2012 to July 2015). Searches of the United States National Library of Medicine ClinicalTrials.gov registry were also conducted. Risk of bias assessments were undertaken to assess data strength and validity.ResultsProposed biosimilars were identified in 23 studies (36 publications) in oncology and ten studies in 14 publications in oncology and chronic inflammatory diseases for bevacizumab, rituximab, and trastuzumab originators. Based on our review of the included published studies, and as inferred from the conclusions of study authors, the identified proposed biosimilars exhibit close similarity to their originators. Published data were also retrieved on intended copies of rituximab. It remains unclear what role these agents may have, as publications on rigorous clinical studies are lacking for these molecules.ConclusionWhile biosimilar products have the potential to improve patient access to important biologic therapies, robust evidence of outcomes for monoclonal antibody biosimilars in treating cancer patients, including data from comparative efficacy and safety trials, is not yet available in the published literature. Significant data gaps exist, particularly for intended copies, which reinforces the need to maintain a clear differentiation between these molecules and true biosimilars. As more biosimilars become available for use, it will be important for stakeholders to understand fully the robustness of overall evidence used to demonstrate biosimilarity and gain regulatory approval.

Evaluating imbalances of adverse events during biosimilar development

ABSTRACT Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.

Abstract P4-21-19: Systematic review of clinical trials for monoclonal antibody biosimilars in HER2-positive breast cancer

Background: A number of proposed trastuzumab (TRAS) biosimilars are now in development for HER2-overexpressing breast cancer treatment. The purpose of this study was to systematically collate all published clinical data to assess the weight of available evidence for TRAS biosimilars in HER2-positive (+) breast cancer (BC), and to identify additional studies, not captured in the scientific literature, to support informed decision-making by healthcare stakeholders, as well as to raise awareness of ongoing developments within the field. Methods: MEDLINE®, Embase® and ISI Web of Science® were searched from inception to Sept 3, 2015. Conference proceedings (n=17) were searched from 2012 to Jul 31, 2015. Studies disclosing potential use of proposed biosimilars in the treatment of HER2+ BC were screened and categorized by originator and study type (English language only). To assess data strength and validity, risk of bias assessments were conducted. The ClinicalTrials.gov (CT.gov) registry was searched to identify any planned/ongoing/complete biosimilar trials in HER2+ BC. Results: On the analysis cut-off date, a total of 7 clinical studies (12 publications) were identified for proposed biosimilars of TRAS. The biosimilars identified for TRAS with published clinical data were BCD-022, CT-P6, FTMB and PF-05280014. For BCD-022, a pharmacokinetics (PK)/safety study in HER2+ BC (N=46) evaluating BCD-022 compared to TRAS, demonstrated equivalence between the two treatments. A PK/safety study (N=174) and comparative safety/efficacy study (N=475) of CT-P6 in HER2+ BC patients both provided evidence of PK equivalence, safety, and efficacy of the proposed biosimilar in this patient population. Bioequivalence of FTMB (versus TRAS) was also reported based on the results of a PK/safety study (N=118) in healthy subjects. For PF-05280014, a PK/safety study (N=105) in healthy volunteers demonstrated equivalence with TRAS. One published comparative safety/efficacy study protocol for PF-05280014 versus TRAS was identified for first-line treatment of patients with HER2+ BC (estimated [E]:N=690), and a second PK/efficacy/safety protocol for neoadjuvant BC treatment (E:N=220) was also published. A number of other planned studies were identified in CT.gov. These included 4 comparative safety/efficacy studies in HER2+ BC evaluating ABP 980 (E:N=808), CT-P6 (N=383/N=532), SB3 (E:N=806) and 2 PK/safety studies (BCD-022 [E:N=206], CT-P6 [E:N=174]) in women with BC. Two studies investigating PK and safety in healthy volunteers were also identified (PF-05280014 [E:N=162], SB3 [E:N=109]). Conclusions: This systematic review provides an unbiased synthesis of available evidence for proposed TRAS biosimilars in HER2+ BC, including data to support clinical similarity. The available clinical data for the 4 proposed biosimilars (BCD-022, CT-P6, FTMB and PF-05280014) investigated in a total of 918 healthy subjects or patients indicated highly comparable PK, safety, or efficacy profiles, versus TRAS. Additional data are required to fully evaluate the clinical similarity for proposed TRAS biosimilars, and the completion of several ongoing comparative trials are expected to provide further assurance of safety and efficacy in specific patient populations. Citation Format: Jacobs I, Isakov L, Vana AM, Coiro J, Zacharchuk C, Ewesuedo R. Systematic review of clinical trials for monoclonal antibody biosimilars in HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-19.

Abstract OT3-1-02: A Phase 3 randomized, double-blind trial comparing PF-05280014 + docetaxel and carboplatin vs. trastuzumab + docetaxel and carboplatin for neoadjuvant treatment of operable HER2+ breast cancer

Background : PF-05280014 is being developed as a potential biosimilar to trastuzumab. PF-05280014 demonstrated similarity to trastuzumab in nonclinical evaluations. In a Phase I trial in healthy subjects, pharmacokinetic (PK) characteristics and safety profile of PF-05280014 were similar to those of trastuzumab. The goal of this Phase 3 trial is to demonstrate that the efficacy and safety of PF-05280014 + docetaxel and carboplatin are similar to those of trastuzumab sourced from the EU (trastuzumab-EU) + docetaxel and carboplatin in the neoadjuvant treatment of women with HER2-positive operable breast cancer. Trial design : In this randomized, double-blind trial, subjects will be randomized (1:1) with stratification by primary tumor size ( 2 ) and carboplatin (target area under the curve [AUC]: 6 mg/mL/min; 30- to 60-minute infusion) every 3 weeks for 6 treatment cycles. The primary objective is to compare the percentages of patients with Cycle 5 C trough (trastuzumab serum trough concentration) >20 μg/mL in the neoadjuvant setting. Secondary objectives include measures of tumor control, safety, immunogenicity, PK, and to explore the relationship between drug exposure and pathologic complete response (pCR). Eligibility criteria : Female subjects with known ER and PR status ≥18 years with confirmed HER2 overexpressing breast cancer and a plan for definitive surgical resection and neoadjuvant chemotherapy, Eastern Cooperative Oncology Group status 0 or 1, normal left ventricular ejection fraction and normal laboratory values are eligible. Key exclusion criteria are bilateral or inflammatory breast cancer; prior treatment, including chemotherapy, endocrine therapy, biologic therapy, radiation or surgery (except diagnostic biopsy); other concomitant active malignancy or history of malignancy in the past 5 years or presence of known distant metastases. All subjects must provide informed consent. Specific aims : The goal of this Phase 3 trial is to demonstrate that PF-05280014 in combination with docetaxel and carboplatin has similarity in PK (trough level) and comparable efficacy and safety versus trastuzumab-EU + docetaxel and carboplatin in subjects with operable HER2-positive breast cancer in the neoadjuvant setting. Statistical methods : This study tests whether percentage of subjects with steady state (Cycle 5) C trough >20 μg/mL of PF-05280014 is similar to that of trastuzumab-EU, using a noninferiority margin of -12.5% tested with α=0.025 (one-sided). Assuming the percentages of subjects reaching steady state is 95% with trastuzumab-EU and 93% with PF-05280014, 188 subjects (94/arm) will be needed to achieve 85% power. Target accrual : 220 subjects. Citation Format: Ira Jacobs, Jennifer Coiro, Fiona Hilton, John Orazem, Richat Abbas, Charles Zacharchuk. A Phase 3 randomized, double-blind trial comparing PF-05280014 + docetaxel and carboplatin vs. trastuzumab + docetaxel and carboplatin for neoadjuvant treatment of operable HER2 + breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-02.

Abstract OT1-1-05: A Phase I pharmacokinetics trial comparing PF-05280014 and trastuzumab in healthy volunteers (REFLECTIONS B327-01)

Background: Trastuzumab is a humanized recombinant monoclonal antibody that selectively binds the extracellular domain of human epidermal growth factor receptor 2 (HER2) and is approved for treatment of breast and gastric cancers. PF05280014 is being developed as a potential biosimilar to trastuzumab. In nonclinical evaluations, PF-05280014 has an identical amino acid sequence to trastuzumab and similar physicochemical and in vitro functional properties. The goal of this phase I trial is to demonstrate the pharmacokinetic similarity of PF-05280014 to trastuzumab sourced from both the United States (trastuzumab-US) and European Union (trastuzumab-EU). Trial design: In this double-blind, parallel group, single dose trial, subjects will be randomized 1:1:1 into 3 arms: PF-05280014; trastuzumab-US, and trastuzumab-EU (NCT01603264). Eligibility: Healthy male volunteers, 18–55 years of age with normal left ventricular ejection fraction are eligible. Multiple exclusion criteria common to Phase 1 trials are in effect. All subjects must provide informed consent. Aims: The primary objectives are to demonstrate the pharmacokinetic similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU. Secondary objectives include evaluating the safety, tolerability, and immunogenicity of PF-05280014 compared with US-licensed and EU-approved trastuzumab products. Statistical methods: Pharmacokinetic similarity will be demonstrated if the 90% confidence interval of the ratio of the area under the concentration-versus-time curve from time 0 to the last time point with quantifiable concentration (AUCT) and maximum concentration (Cmax) of PF-05280014 to both trastuzumab-US and trastuzumab-EU are within 80%–125%. At least 93 subjects, 31/arm, will be needed to provide >81% power to demonstrate pharmacokinetic similarity for all comparisons. The planned enrolment is 105 subjects to account for subjects who may not complete the full follow-up period. The intent-to-treat (ITT) population is defined as all subjects who are randomized to receive treatment. The modified ITT population is defined as all subjects who are randomized and receive at least one dose of treatment and will be used to assess safety, tolerability, and immunogenicity. The per-protocol population is defined as all subjects who are randomized to and receive treatment and do not have any major protocol violations and will be used for the primary evaluation of pharmacokinetic parameters. Accrual: The target accrual is 105 subjects; present accrual is 17subjects. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-05.