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Phase I Study to Determine the Maximum Tolerable Dose of BAY94-9343 in Patients With Advanced Solid Tumors.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01439152
Recruitment Status : Completed
First Posted : September 23, 2011
Last Update Posted : July 9, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Description
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Brief Summary:
BAY94-9343 was an antibody-drug conjugate (ADC) directed against the cancer antigen mesothelin on tumor cells.

Condition or disease Intervention/treatment Phase
Oncology Drug: BAY94-9343 Drug: BAY94-9343 (Expansion) Drug: BAY94-9343 (1.8 mg/kg) Drug: BAY94-9343 (2.2 mg/kg) Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 148 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Phase I Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Maximum Tolerated Dose of the Anti-mesothelin Antibody Drug Conjugate BAY94-9343 in Subjects With Advanced Solid Tumors
Actual Study Start Date : September 7, 2011
Actual Primary Completion Date : December 31, 2016
Actual Study Completion Date : July 30, 2019
Arms and Interventions
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Arm Intervention/treatment
Experimental: BAY94-9343 (Dose-Escalation)
BAY94-9343 was administered intravenously in this study. The starting dose for this first-in-man study was 0.15 mg/kg administered as a 1 hour infusion every 21 days. (ENROLLMENT CLOSED).
 Drug: BAY94-9343
BAY94-9343 was administered intravenously in this study. The starting dose for this first-in-man study was 0.15 mg/kg administered as a 1 hour infusion every 21 days.
Experimental: BAY94-9343 (Expansion)

After Maximum tolerated dose (MTD) had been defined, expansion cohorts were conducted at the MTD dose. Overall up to 32 subjects were planned to be enrolled in the expansion cohort:

  • Ovarian Carcinoma, 20 subjects
  • Mesothelioma, 6-12 subjects (ENROLLMENT CLOSED).
 Drug: BAY94-9343 (Expansion)
BAY94-9343 was administered intravenously in this study. The dose for this expansion cohort was 5.5mg/kg administered as a 1 hour infusion every 21 days.
Experimental: BAY94-9343 (1.8 mg/kg)
This part of study was randomized and open-label. BAY94-9343 in two parallel dose cohorts of twenty (20) patients with recurrent platinum-resistant or platinum partially-sensitive ovarian cancer and up to four (4) patients with advanced malignant epithelioid peritoneal mesothelioma and eight (8) patients with advanced pleural mesothelioma.
 Drug: BAY94-9343 (1.8 mg/kg)
BAY94-9343 was administered intravenously in this study. The dose for this cohort was 1.8 mg/kg administered as a 1 hour infusion every week for 3 weeks.
Experimental: BAY94-9343 (2.2 mg/kg)
This part of study was randomized and open-label. BAY94-9343 in two parallel dose cohorts of twenty (20) patients with recurrent platinum-resistant or platinum partially-sensitive ovarian cancer and up to four (4) patients with advanced malignant epithelioid peritoneal mesothelioma and eight (8) patients with advanced pleural mesothelioma.
 Drug: BAY94-9343 (2.2 mg/kg)
BAY94-9343 was administered intravenously in this study. The dose for this cohort was 2.2 mg/kg administered as a 1 hour infusion every week for 3 weeks.


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of DLT (dose limiting toxicity) of BAY 94-9343 [ Time Frame: At the end of Cycle 1 Day21 ]
  2. Determination of the Pharmacokinetic profile of BAY94-9343 and its metabolites (ADC, Total Antibody, DM4 and DM4-Me) [ Time Frame: Cycle 1 and Cycle 3: pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8, (24), 48, (96), 168, 336 and 504 hours after start of infusion ]
    Q3W Arm: Cmax, AUC (0-504), AUC (0-tlast), tmax, t1/2 and AUC (Cycle 1 only) Q3W: Cycle 1 and Cycle 3: pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8, (24), 48, (96), 168, 336 and 504 hours after start of infusion QW Arm:Cmax, AUC(0-168) and tmax) QW: Cycle 1 and Cycle 3: pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8, 24, 48 and 168 hours after start of infusion


Secondary Outcome Measures :
  1. Biomarker evaluation: Plasma concentrations of soluble mesothelin and Cytokeratin 18 (CK18) [ Time Frame: C1D1: pre-dose, 24, 48, and 168h after start of infusion; C2D1: pre-dose, 4 and 168h after start of infusion; C3D1: pre-dose, 24, 48, and 168h after start of infusion; C4 and every even cycle: pre-dose until Implementation of Am 6 ]
  2. Tumor response: assessment of best response and PFS (progression free survival) according to RECIST (Response Evaluation Criteria in Solid Tumours) 1.1 [ Time Frame: 1 year/Screening; Within 5 days before the end of every even cycle until Cycle 8 (Cycle 2, Cycle 4, etc.); Within 5 days before the end of every 4th cycle after Cycle 8 (Cycle 12, 16, etc.); end of treatment ]
  3. Immunogenicity assessment: assessment of Anti-drug antibody (ADA) formation and neutralizing antibodies (NAs) against anetumab ravtansine [ Time Frame: 1 year / Cycle 1, 2 and 3 Day 1: pre-dose; Day 1 of every even cycle starting from Cycle 4 (Cycle 4, 6, 8 etc.): pre-dose until implementation of Am 6 ]
  4. Biomarker evaluation - Levels of mesothelin expression in tumor tissue [ Time Frame: Anytime prior to general screening ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All subjects must be ≥ 18 years at the first screening examination / visit
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
  • Life expectancy of at least 12 weeks

  • Histologically or cytologically documented invasive epithelial ovarian, primary peritoneal, or fallopian tube cancer (tumors with pseudomyxomatous or mucinous histology are excluded) or advanced predominantly epithelioid peritoneal mesothelioma.

    -- Ovarian cancer must have relapsed >0 months and ≤ 12 months of the prior platinum-based chemotherapy regimen (platinum resistant and partially platinum sensitive).

  • All patients must provide the tumor tissue sample [Formalin Fixed Paraffin Embedded (FFPE) slides] from archival tissue or fresh biopsy collected any time before the general screening under the separate informed consent.

  • Mesothelin expression in the tumor tissue from archival or fresh biopsy samples defined as the membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on at least 30% of tumor cells.

    -- Mesothelin expression must be determined by the validated Investigational Use Only (IUO) assay for ovarian cancer or the prototype immunohistochemistry (IHC) assay for mesothelioma at Ventana at any time before the general screening in patients who had signed a separate informed consent for tumor tissue analysis for mesothelin expression.

  • No more than 3 prior lines of systemic cytotoxic therapy for patients with advanced peritoneal or pleural mesothelioma or
  • No more than 5 prior lines of systemic cytotoxic therapy for patients with ovarian cancer
  • Possible intraperitoneal administration of cytotoxics during surgery will not count as systemic cytotoxic therapy in either case.
  • Measurable disease with at least one lesion that can be accurately measured in at least one dimension according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

exclusion Criteria:

  • More than 3 prior lines of systemic cytotoxic therapy for patients with advanced peritoneal or pleural mesothelioma
  • More than 5 prior lines of systemic cytotoxic therapy for patients with ovarian cancer
  • Other systemic anticancer therapies (molecular-targeted, immunotherapy etc.) may be acceptable after the consultation between the Investigator and the Bayer Medical Expert.
  • Intraperitoneal administration of cytotoxic anticancer agents during tumor surgery will not count as systemic cytotoxic therapy in this context.
  • Prior local radiotherapy is allowed if it is completed at least 4 weeks prior to the first dose of study drug and the subject has evaluable lesions not previously irradiated.
  • Anticancer chemotherapy, experimental cancer therapy, or immunotherapy within 2 weeks of start of first dose. Anticancer therapy is defined as any agent or combination of agents with clinically proven anti tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints.
  • Radiotherapy to the target lesions within 4 weeks prior to the first BAY94-9343 infusion, if the subject has evaluable tumor lesions not previously irradiated.
  • Use of strong inhibitors of P-glycoprotein (transporter) (P-gp) (e.g., ritonavir, cyclosporine, verapamil, and dronedarone) is prohibited from Day -14 and for the duration of the study.
  • Impaired cardiac function or clinically significant cardiac disease [i.e., congestive heart failure (CHF) New York Heart Association (NYHA) Class III or IV].
  • Left ventriculat ejection fraction (LVEF) <50 % [as measured at screening by Multiple Gated Acquisition scan (MUGA) or echocardiogram].
  • Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mmHg, despite optimal medical management.
  • Mild blurry vision, either age-related or due to ocular or systemic disorder (e.g. diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at the discretion of the ophthalmologist if deemed as no constituting a predisposition to drug-induced corneal deposits and blurry vision
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01439152


Locations
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United States, Connecticut
New Haven, Connecticut, United States, 06520-8063
United States, Illinois
Chicago, Illinois, United States, 60637
United States, Maryland
Bethesda, Maryland, United States, 20892
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Nashville, Tennessee, United States, 37203
United States, Texas
Dallas, Texas, United States, 75251
Houston, Texas, United States, 77030
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01439152    
Obsolete Identifiers: NCT01479335
Other Study ID Numbers: 15051
First Posted: September 23, 2011    Key Record Dates
Last Update Posted: July 9, 2021
Last Verified: July 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Oncology
Solid tumors
Antibody drug conjugate (ADC)
Treatment Emergent Adverse Events
Mesothelin
Additional relevant MeSH terms:
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Neoplasms
Maytansine
Anetumab ravtansine
Immunoconjugates
Immunologic Factors
Physiological Effects of Drugs
 Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action