Phase 1b Multi-indication Study of Anetumab Ravtansine in Mesothelin Expressing Advanced Solid Tumors

Bayer173 enrolled

Overview

The key purpose of the main part of the study is to assess efficacy and safety of anetumab ravtansine as monotherapy or combination therapy for mesothelin expressing advanced solid tumors. The main purpose of the safety lead-in (dose-finding) part of the study is to determine the safety and tolerability of anetumab ravtansine in combination with cisplatin and in combination with gemcitabine, and to determine the MTD of anetumab ravtansine in combination with cisplatin for mesothelin expressing advanced cholangiocarcinoma and in combination with gemcitabine for mesothelin expressing advanced adenocarcinoma of the pancreas. Patients will receive anetumab ravtansine every three weeks in monotherapy for most indications. In cholangiocarinoma and adenocarinoma of the pancreas, 3-weekly anetumab ravtansine is administered in combination with cisplatin or gemcitabine respectively (both administered in a 2 week on / 1 week off schedule). Treatment will continue until disease progression or until another criterion for withdrawal is met. .Efficacy will be measured by evaluating the tumor's objective response rate. Radiological tumor assessments will be performed at defined time points until the patient's disease progresses. Blood samples will be collected for safety, pharmacokinetic and biomarker analysis. Archival or fresh biopsy tissue will also be collected for mesothelin expression testing and biomarker analyses.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

173

Conditions

Neoplasms

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Availability of tumor tissue for mesothelin expression testing and for further biomarker analysis * Histologically-confirmed, mesothelin-expressing metastatic or advanced non-metastatic disease (tumour type specific inclusion criteria) * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (or for thymic carcinoma, at least one measurable lesion per International Thymic Malignancy Interest Group (ITMIG) modified RECIST 1.1 criteria * Adequate bone marrow, liver, renal and coagulation function * Left ventricular ejection fraction (LVEF) ≥ 50% of the lower limit of normal (LLN) according to local institutional ranges * Eastern Cooperative Oncology Group (ECOG) 0 or 1 Exclusion Criteria: * Exposure to more than one prior anti-tubulin/microtubule agent * Corneal epitheliopathy or any eye disorder that may predispose the patients to this condition * Symptomatic Central nervous system (CNS) metastases and/or carcinomatous meningitis * Contraindication to both CT and MRI contrast agents * Active hepatitis B or C infection * Pregnant or breast-feeding patients * Tumor type specific exclusion criteria

Outcomes

Primary Outcomes

Number of patients in the safety lead-in (SLI) phase who completed Cycle 1 or had a DLT and were not replaced.

During SLI, patients with cholangiocarcinoma received anetumab ravtansine in combination with cisplatin and patients with pancreatic adenocarcinoma received anetumab ravtansine in combination with gemcitabine. The highest dose of anetumab ravtansine that can be given so that not more than 1 out of 6 patients experiences a dose-limiting toxicity (DLT) during the DLT evaluation period were declared as the MTD for anetumab ravtansine in combination with cisplatin or with gemcitabine.

Time frame: At least 3 weeks after the last patient starts treatment

Objective response (qualitative improvement from baseline) of anetumab ravtansine for monotherapy and combination therapy in mesothelin expressing advanced solid tumors

A patient is a responder if the patient has a best response compared to baseline of complete response (CR) or partial response (PR) among all post-baseline tumor assessments, as determined per RECIST 1.1 criteria (ITMIG modified RECIST 1.1 criteria for thymic carcinoma)

Time frame: Up to approximately 26 months after patient starts treatment

Durable disease control (lack of progression from baseline) of anetumab ravtansine in indications pancreatic and gastric cancer (co-primary endpoint)

A patient experiences durable disease control if the patient has a tumor response compared to baseline of CR, PR or stable disease (SD) among the post-baseline tumor assessments made at least 180 days from first treatment, without prior disease progression

Time frame: Up to approximately 26 months after patient starts treatment

Secondary Outcomes

Number of serious and non-serious adverse events (AEs)

Include treatment-emergent AEs, SAEs, treatment-related AEs, AEs of special interest, and deaths.

Time frame: Approximately 26 months (Until 30 days after the last day of study treatment, or until later resolution of adverse events or determination by the investigator that the event will not improve)

Disease control rate (DCR)

The DCR is defined as the number of patients with disease control divided by the number of treated patients.

Time frame: Up to approximately 24 months after last patient starts treatment, or until earlier disease progression [assessed every 6 weeks for the first 6 months, every 9 weeks until end of year 1 and every 12 weeks thereafter]

Duration of response (DOR)

DOR is defined in responders as the time from documentation of tumor response (CR or PR) to earlier of disease progression or death

Durable response rate (DRR)

A durable responder is defined as a responder (CR or PR) with a duration of response per RECIST 1.1 criteria (ITMIG modified RECIST 1.1 criteria for thymic carcinoma) of 180 days or more. The DRR is the number of durable responders divided by the number of treated patients.

Progression free survival (PFS)

PFS is defined as time from start of treatment until disease progression according to RECIST 1.1 (ITMIG modified RECIST 1.1 criteria for thymic carcinoma) or death.

Durable disease control rate (DDCR) of anetumab ravtansine in indications other than pancreatic and gastric cancer

A patient experiences durable disease control if the patient has a tumor response of CR, PR or SD with CR, PR or SD assessed at least 180 days from first treatment, without prior progression.