A Study to Determine Best Tumor Response With Trastuzumab Emtansine in Human Epidermal Growth Factor Receptor 2 (HER2) Overexpressing Solid Tumors

Phase 2

Completed

• Conditions: Bladder Cancer; Pancreas Cancer; Cholangiocellular Carcinoma
• Interventions: Drug: Trastuzumab Emtansine

• Registration Number: NCT02999672
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This multicenter, non-randomized, Phase II study will assess the efficacy, safety, and pharmacokinetics of trastuzumab emtansine in participants with HER2 overexpressing locally advanced (unresectable and not treatable with curative intent) or metastatic urothelial bladder cancer (UBC), locally advanced (unresectable and not treatable with curative intent) or metastatic pancreatic cancer/cholangiocarcinoma with advanced disease where cure is no longer possible and where no other treatment options are available anymore. Participants will receive intravenous (IV) infusion of trastuzumab emtansine as Regimen A (2.4 milligrams per kilogram \[mg/kg\], weekly \[qw\]) or Regimen B (3.6 mg/kg, every 3 weeks \[q3w\]) until unacceptable toxicity, withdrawal of consent, disease progression (PD), or death, whichever occurs first. Based on tolerability and safety aspects, steering committee and Independent Data Monitoring Committee (iDMC) will decide on expansion of the study to include more participants with other carcinoma types.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-12-19
• Study First Submitted QC: 2016-12-19
• Study First Posted: 2016-12-21
• Study Start: 2016-12-23
• Primary Completion: 2018-04-10
• Study Completion: 2018-04-10
• Results First Submitted: 2019-04-08
• Status Verified: 2019-07
• Results First Submitted QC: 2019-07-22
• Last Update Submitted: 2019-07-22
• Results First Posted: 2019-08-28
• Last Update Posted: 2019-08-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Histologically centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ in greater than or equal to [>/=] 30 percent [%] of tumor cells): locally advanced (unresectable and not treatable with curative intent), or metastatic UBC or locally advanced (unresectable and not treatable with curative intent) or metastatic pancreatic cancer/cholangiocarcinoma
• There must be no standard treatment options available for participants with the above HER2 overexpressing tumors and they must have undergone at least one prior platinum-based treatment for locally advanced (unresectable and not treatable with curative intent) or metastatic tumor (Note: for pancreatic cancer/cholangiocarcinoma, prior treatments are not required to be platinum-based.)
• Participant's lesion should be measurable according to RECIST V1.1 on diagnostic computed tomography (CT) scan/magnetic resonance imaging (MRI); Target lesion(s) should not have been previously irradiated
• At least one formalin-fixed paraffin-embedded (FFPE) biopsy of the primary tumor and/or from a metastatic site is required
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
• No significant cardiac history and a current left ventricular ejection fraction (LVEF) >/=50%
• Adequate organ function
• Life expectancy of at least 12 weeks

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Exclusion Criteria

• Participants with previous exposure to HER2-targeted therapies in any setting
• Participants showing histologically confirmed focal HER2-expression, that is, less than (<) 30% of positively stained tumor cells
• Participants with brain metastasis as the sole site of metastatic disease and/or are symptomatic or require therapy to control symptoms
• Current uncontrolled hypertension (systolic greater than [>] 150 millimeters of mercury [mmHg] and/or diastolic >100 mmHg)
• Current unstable angina pectoris
• History of symptomatic congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria or ventricular arrhythmia that requires treatment
• History of myocardial infarction within the last 6 months
• Peripheral neuropathy, Grade >/=3
• Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
• Current severe, uncontrolled systemic disease
• History of other malignancy within the last 5 years
• Concurrent, serious, uncontrolled infections or current known infection with human immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C
• Known prior severe hypersensitivity to trastuzumab and trastuzumab emtansine or the excipients of the investigational medicinal product (IMP)
• Clinically significant bleeding within 30 days before enrollment
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
• Concurrent participation in any other therapeutic clinical trial

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1 (UBC)	Trastuzumab Emtansine	First six participants with locally advanced (unresectable and not treatable with curative intent) or metastatic UBC will initially receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w).
Cohort 2 (Pancreatic cancer/cholangiocarcinoma)	Trastuzumab Emtansine	First six participants with metastatic pancreatic cancer/cholangiocarcinoma will receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w).

Primary Outcome Measures

Name	Time	Method
Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).	Baseline up to PD/recurrence or death, whichever occurs first (up to approximately 18 months)	BOR was defined as having best objective response as complete response (CR) or partial response (PR), as assessed by investigator and confirmed at least 28 days after initial response, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of CR or PR are reported.

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Baseline up to PD/recurrence or death, whichever occurs first (up to approximately 18 months)	PFS was the time from inclusion in the study to the date of first documented PD or death from any cause, whichever occurred first. Participants without event were censored at the date of the last tumor assessment where non-progression was documented. If a participant received a second anti-cancer therapy without prior documentation of disease progression, the participant was censored at the date of last tumor assessment before starting new chemotherapy. PD was defined as at least a 20% increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.
Overall Survival (OS)	Baseline up to PD/recurrence or death, whichever occurs first (up to approximately 18 months)	OS was determined as the time from beginning of treatment to death from any cause.
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)	Baseline up to approximately 18 months	Incidence, type and severity of all adverse events (AEs) and serious adverse events (SAEs), based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03).
Percentage of Participants With Drug-induced Liver Injury Meeting Hy's Law Criteria	Baseline up to approximately 18 months	Participants from both cohorts (UBC and Pancreatic cancer/cholangiocarcinoma) were analyzed for drug-induced liver injury following Hy's Law. Hy's Law criteria for potential drug-induced liver injury includes an elevated ALT (alanine aminotransferase) or AST (aspartate aminotransferase) in combination with either elevated bilirubin or clinical jaundice.
Plasma/Serum Concentrations of Trastuzumab Emtansine	Regimen A: predose (0 minutes [min]) and 15-30 min postinfusion on Days (D) 1, 8, 15 of Cycle (C) 1 and D1C4; predose on D1C2. Regimen B: predose and 15-30 min postinfusion on D1C1 and D1C4; predose on D1C2. 1 Cycle=21 days	Samples for evaluation of trastuzumab emtansine, DM1, and total trastuzumab were obtained from all participants from both cohorts at specified time points.

Trial Locations

Locations (16)

Complejo Hospitalario de Navarra; 🇪🇸 Pamplona, Navarra, Spain

IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica; 🇮🇹 Meldola, Emilia-Romagna, Italy

Narodny onkologicky ustav; 🇸🇰 Bratislava, Slovakia

UMCG; 🇳🇱 NL -groningen, Netherlands

Irccs Ospedale San Raffaele;Oncologia Medica; 🇮🇹 Milano, Lombardia, Italy

A.O.U.I. VERONA-OSPEDALE POLICLINICO G.B. ROSSI BORGO ROMA;ONCOLOGIA MEDICA-d.U.; 🇮🇹 Verona, Veneto, Italy

Hospital Duran i Reynals; Oncologia; 🇪🇸 Barcelona, Spain

IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima; 🇮🇹 Padova, Veneto, Italy

Antoni van Leeuwenhoek Ziekenhuis; 🇳🇱 Amsterdam, Netherlands

Amsterdam UMC Location VUMC; 🇳🇱 Amsterdam, Netherlands

Erasmus MC - Centrum; 🇳🇱 NL -rotterdam, Netherlands

Hospital Univ Vall d'Hebron; Servicio de Oncologia; 🇪🇸 Barcelona, Spain

Hospital Regional Universitario Carlos Haya; Servicio de Oncologia; 🇪🇸 Malaga, Spain

Irccs Istituto Europeo Di Oncologia (IEO); Cure Mediche; 🇮🇹 Milano, Lombardia, Italy

Hospital Ramon y Cajal; Servicio de Oncologia; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; Servicio de Oncologia; 🇪🇸 Madrid, Spain