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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

Tracking Information
First Submitted Date  ICMJE September 1, 2011
First Posted Date  ICMJE September 23, 2011
Last Update Posted Date July 9, 2021
Actual Study Start Date  ICMJE September 7, 2011
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
  • Incidence of DLT (dose limiting toxicity) of BAY 94-9343 [ Time Frame: At the end of Cycle 1 Day21 ]
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 22, 2011)
  • Determination of maximum tolerated dose [ Time Frame: 2 years / assessment of dose limiting toxicities in Cycle 1 ]
  • Determination of the Pharmakokinetic profile of BAY94-9343 and its metabolites [ Time Frame: 2 years / Cycle 1 Day 1: PK samples at 0, 0.5, 1, 1.5, 2, 3, 5, 8, 24, 48, 96, 168, 336, 504 hours after start of infusion; Cycle 3 Day 1: 0, 0.5, 1, 1.5, 2, 3, 5, 8, 48, 96, 168, 336, 504 hours after start of infusion. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2021)
  • 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 ]
  • 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 ]
  • 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 ]
  • Biomarker evaluation - Levels of mesothelin expression in tumor tissue [ Time Frame: Anytime prior to general screening ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2011)
  • Biomarker evaluation: mesothelin tumor levels, soluble mesothelin plasma levels [ Time Frame: 2 years / baseline, Days 1, 2, 3, 5, 15 of Cycle, 1, Days 1 and 15 of all subsequent cycles ]
  • Tumor response: assessment of best response, TTP (time to progression), and PFS (progression free survival) according to RECIST (Response Evaluation Criteria in Solid Tumours) 1.1 [ Time Frame: 2 years / assessment at baseline, every 6 weeks of for the first 8 cylces, afterwards every 12 weeks ]
  • Immunogenicity assessment: assessment of anti BAY 94-9343 antibodies [ Time Frame: 2 years / Cycle 1 Day 1 (pre-dose), Cycle 1 Day 8, Cycle 2 Day 1 and Day 1 of every even cycle (4, 6, 8 etc.) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I Study to Determine the Maximum Tolerable Dose of BAY94-9343 in Patients With Advanced Solid Tumors.
Official Title  ICMJE 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
Brief Summary BAY94-9343 was an antibody-drug conjugate (ADC) directed against the cancer antigen mesothelin on tumor cells.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Oncology
Intervention  ICMJE
  • 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.
  • 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.
  • 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.
  • 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.
Study Arms  ICMJE
  • 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).
    Intervention: Drug: BAY94-9343
  • 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).
    Intervention: Drug: BAY94-9343 (Expansion)
  • 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.
    Intervention: Drug: BAY94-9343 (1.8 mg/kg)
  • 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.
    Intervention: Drug: BAY94-9343 (2.2 mg/kg)
Publications * Hassan R, Blumenschein GR Jr, Moore KN, Santin AD, Kindler HL, Nemunaitis JJ, Seward SM, Thomas A, Kim SK, Rajagopalan P, Walter AO, Laurent D, Childs BH, Sarapa N, Elbi C, Bendell JC. First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors. J Clin Oncol. 2020 Jun 1;38(16):1824-1835. doi: 10.1200/JCO.19.02085. Epub 2020 Mar 26.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 20, 2020)
148
Original Estimated Enrollment  ICMJE
 (submitted: September 22, 2011)
58
Actual Study Completion Date  ICMJE July 30, 2019
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01439152
Other Study ID Numbers  ICMJE 15051
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Bayer
Original Responsible Party Head Clinical Pharmacology, Bayer Healthcare AG
Current Study Sponsor  ICMJE Bayer
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP