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A Study of RO6927005 Either As Monotherapy (Part A) or in Combination With Gemcitabine and Nab-Paclitaxel (Part B) to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Clinical Activity in Patients With Mesothelin-positive Metastatic and/or Locally Advanced Malignant Solid Tumors

NCT02317419

Description:

This is a first-in-human, open-label, multi-center, Phase 1 study of RO6927005. The study will establish the safety and tolerability profile of RO6927005 and will be conducted in two parts. In Part A, the first dose escalations will be carried out using cohorts of 1 patient. Single patient cohorts will be used to investigate increasing doses until a first dose-limiting toxicity (DLT) is reached or until grade-2 related toxicity (except infusion-related reactions), whichever comes first. At least 3 patients will be enrolled in each cohort thereafter, which, if required, can be expanded with additional patients. Part B of the study will consist of a multiple ascending dose phase (multiple patients cohorts - >/= 3 patients) followed by an extension phase of RO6927005 given in combination with gemcitabine/nab-paclitaxel. Preliminary clinical activity will be explored throughout the study. Patients will be treated until disease progression and/or lack of clinical benefit, unacceptable toxicities, withdrawal from treatment for other reasons, death, pregnancy or termination of the study by the Sponsor, whichever comes first.

Related Conditions:
  • Malignant Solid Tumor
  • Pancreatic Ductal Adenocarcinoma
  • Pleural Mesothelioma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

A Study of RO6927005 Either As Monotherapy (Part A) or in Combination With <span class="go-doc-concept go-doc-intervention">Gemcitabine</span> and <span class="go-doc-concept go-doc-intervention">Nab-Paclitaxel</span> (Part B) to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Clinical Activity in Patients With Mesothelin-positive Metastatic and/or Locally Advanced Malignant Solid Tumors

Title

  • Brief Title: A Study of RO6927005 Either As Monotherapy (Part A) or in Combination With Gemcitabine and Nab-Paclitaxel (Part B) to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Clinical Activity in Patients With Mesothelin-positive Metastatic and/or Locally Advanced Malignant Solid Tumors
  • Official Title: PHASE IA/IB, OPEN-LABEL, MULTICENTER, MULTIPLE ASCENDING DOSE STUDY FOLLOWED BY AN EXTENSION PHASE TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND ACTIVITY OF RO6927005, AN ANTI-MESOTHELIN (MSLN) RECOMBINANT CYTOLYTIC FUSION PROTEIN (cFP), ADMINISTERED EITHER ALONE (PART A) OR IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL (PART B) IN PATIENTS WITH MESOTHELIN-POSITIVE METASTATIC AND/OR LOCALLY ADVANCED MALIGNANT SOLID TUMORS
  • Clinical Trial IDs

    NCT ID: NCT02317419

    ORG ID: BP29387

    NCI ID: 2014-002935-32

    Trial Conditions

    Solid Cancers

    Trial Interventions

    Drug Synonyms Arms
    RO6927005 Part A - Extension Phase Group 1, Part A - Extension Phase Group 2, Part A - MAD phase RO6927005 monotherapy
    RO6927005 Part B - Extension Phase, Part B - MAD phase
    gemcitabine Part B - Extension Phase, Part B - MAD phase
    nab-paclitaxel Part B - Extension Phase, Part B - MAD phase

    Trial Purpose

    This is a first-in-human, open-label, multi-center, Phase 1 study of RO6927005. The study
    will establish the safety and tolerability profile of RO6927005 and will be conducted in two
    parts.

    In Part A, the first dose escalations will be carried out using cohorts of 1 patient. Single
    patient cohorts will be used to investigate increasing doses until a first dose-limiting
    toxicity (DLT) is reached or until grade-2 related toxicity (except infusion-related
    reactions), whichever comes first. At least 3 patients will be enrolled in each cohort
    thereafter, which, if required, can be expanded with additional patients. Part B of the
    study will consist of a multiple ascending dose phase (multiple patients cohorts - >/= 3
    patients) followed by an extension phase of RO6927005 given in combination with
    gemcitabine/nab-paclitaxel.

    Preliminary clinical activity will be explored throughout the study. Patients will be
    treated until disease progression and/or lack of clinical benefit, unacceptable toxicities,
    withdrawal from treatment for other reasons, death, pregnancy or termination of the study by
    the Sponsor, whichever comes first.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Part A - Extension Phase Group 1 Experimental Mesothelin-positive solid tumors, excluding MPM and PDA RO6927005
    Part A - Extension Phase Group 2 Experimental Mesothelin-positive malignant mesothelioma (MPM) RO6927005
    Part A - MAD phase RO6927005 monotherapy Experimental tumors known to be mesothelin expressing / mesothelin-positive tumors RO6927005
    Part B - Extension Phase Experimental mesothelin-positive metastatic and/or advanced PDA RO6927005, gemcitabine, nab-paclitaxel
    Part B - MAD phase Experimental mesothelin-positive metastatic and/or advanced PDA RO6927005, gemcitabine, nab-paclitaxel

    Eligibility Criteria

    Inclusion Criteria:

    - Written informed consent

    - Age >/= 18 years

    - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

    - Patients for whom no standard curable therapy exists

    - Life expectancy of >/= 12 weeks

    - Last dose of systemic anti-neoplastic therapy > 21 days prior to first RO6927005
    infusion

    - Palliative radiotherapy is allowed up to 2 weeks before the first RO6927005 infusion;
    palliative 8 Gy radiotherapy is allowed during therapy.

    - All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical
    procedure must have resolved to Grade </= 1, except alopecia (any grade) and Grade 2
    peripheral neuropathy

    - Adequate hematological, liver, and renal function

    - Negative serum or urine pregnancy test within 7 days prior to study treatment in
    premenopausal women and women </= 2 years after menopause (menopause is defined as
    amenorrhea for >/= 2 years)

    - Agreement to use adequate contraceptive methods per protocol

    - Measurable and/or evaluable disease as per the Response Evaluation Criteria In Solid
    Tumors (RECIST) version 1.1) [Groups 1, 2 of Part A and Group 3 of Part B]

    Inclusion Criteria Part A: MAD

    - Metastatic and/or locally advanced malignant solid tumors enriched in tumor types
    known to be mesothelin expressing

    - Archival sample or fresh biopsy or tumor effusion must be available for retrospective
    mesothelin analysis

    Inclusion Criteria Part A: MAD and Extension Phase (Group 1 and Group 2)

    - Histologically confirmed metastatic and/or advanced malignant mesothelin-positive
    solid tumors as determined by central pathology lab review

    - Patients must be willing to provide a screening and post-dose biopsy for biomarker
    analysis (extension phase only)

    - Mesothelin-positive refractory/recurrent solid tumors, other than malignant pleural
    mesothelioma (MPM) and pancreatic ductal adenocarcinoma (PDA) (Group 1 only)

    - Mesothelin-positive refractory/recurrent MPM (Group 2 only)

    Inclusion Criteria Part B

    - Histologically confirmed metastatic and/or advanced mesothelin-positive PDA as
    determined by central pathology lab review

    - In the extension phase, patients must be willing to provide a screening and post-dose
    biopsy for biomarker analysis

    Exclusion Criteria:

    - Known or clinically suspected central nervous system (CNS) primary tumors or
    metastases including leptomeningeal metastases; history or clinical evidence of CNS
    metastases unless they have been previously treated, are asymptomatic, and have had
    no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days

    - Evidence of significant, uncontrolled concomitant diseases which could affect
    compliance with the protocol or interpretation of results, including significant
    pulmonary disease other than primary cancer, uncontrolled diabetes mellitus, and/or
    significant cardiovascular disease (such as New York Heart Association Class III or
    IV cardiac disease, myocardial infarction within the last 6 months, unstable
    arrhythmias, unstable angina, or clinically significant pericardial effusion)

    - Active or uncontrolled infections

    - Known HIV or known active HBV or HCV infection

    - Patients with extrapleural pneumonectomy (EPP)

    - Any other diseases, metabolic dysfunction, physical examination finding, or clinical
    laboratory finding giving reasonable suspicion of a disease or condition that would
    contraindicate the use of an investigational drug

    - Major surgery or significant traumatic injury < 28 days prior to the first RO6927005
    infusion (excluding biopsies) or anticipation of the need for major surgery during
    study treatment

    - Dementia or altered mental status that would prohibit informed consent

    - Live attenuated vaccinations 14 days prior to treatment

    - Pregnant or breast-feeding women

    - Known hypersensitivity to any of the components of RO6927005

    - High doses of systemic corticosteroids within 7 days prior to first dosing. High dose
    is considered as > 20 mg of dexamethasone a day (or equivalent) for > 7 consecutive
    days

    Exclusion Criteria (Part B):

    - Patients with contra-indication and/or history of severe hypersensitivity reactions
    to gemcitabine and/or nab-paclitaxel as mentioned in the locally approved label

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Safety: incidence of dose-limiting toxicities, adverse events, laboratory abnormalities; incidence of anti-drug antibodies, abnormal findings on physical examination, infusion-related reactions (composite outcome measure)

    Secondary Outcome Measures

    Pharmacokinetic profile of RO6927005 monotherapy based on free and total plasma RO6927005 concentrations over time (area under the curve)

    Pharmacokinetic profile of RO6927005 in combination with gemcitabine/nab-paclitaxel, based on free and total plasma RO6927005 concentrations over time (area under the curve)

    Efficacy: objective response rate, disease control rate, duration of response, progression-free survival, overall survival (composite outcome measure)

    Trial Keywords