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
| Status: | Completed |
|---|---|
| Conditions: | Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | December 2014 |
| End Date: | August 2015 |
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
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.
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.
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 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 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
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