Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Serono S.A., Geneva
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01016483
First received: November 18, 2009
Last updated: August 22, 2014
Last verified: August 2014
  Purpose

The research trial is testing the experimental treatment MSC1936369B in combination with Gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. The study will be run in two parts:

Safety Run-In: Will determine the Maximum Tolerated Dose (MTD) and the recommended Phase II dose of MSC1936369B, when combined with gemcitabine, in subjects with metastatic pancreatic adenocarcinoma.

Phase II: Will assess the anti-tumor activity of MSC1936369B combined with gemcitabine compared to gemcitabine alone as first line treatment in subjects with metastatic pancreatic adenocarcinoma.


Condition Intervention Phase
Pancreatic Adenocarcinoma
Drug: MSC1936369B (MEK Inhibitor)
Drug: Gemcitabine
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Safety Run-In Part: Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: Days 1, 2, 8, 15, 22, and 29 of Cycle 1 ] [ Designated as safety issue: Yes ]
  • Part 2: Progression-Free Survival (PFS) time [ Time Frame: Evaluations will be performed every 8 weeks up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety Run-In Part: Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Time to Reach Maximum Concentration (tmax) and Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Area Under Curve (AUC) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Apparent Oral Clearance (CL/f) of MSC1936369B [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Oral volume of distribution (V/f) of MSC1936369B and Apparent volume of distribution (V) of gemcitabine [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Renal clearance (CLR) of MSC1936369B and Clearance (CL) of gemcitabine [ Time Frame: Days 1, 2, 8, 15, 22, 23, and 26 of Cycle 1 and Days 1, 8, and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Safety Run-In Part: Levels of pharmacodynamic (Pd) markers (e.g. phospho-ERK in peripheral blood mononuclear cells [PBMCs]) [ Time Frame: Days 1, 2, and 22 of Cycle 1 ] [ Designated as safety issue: No ]
  • Part 2: Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Part 2: Percentage of subjects with best overall response (BOR) [ Time Frame: Evaluations will be performed every 8 weeks up to 5 years ] [ Designated as safety issue: No ]
    Best overall response is defined as the presence of at least one Complete Response (CR) or Partial Response (PR) (using Response Evaluation Criteria In Solid Tumors [RECIST v1.0]) during treatment.

  • Part 2: Percentage of subjects with clinical benefit [ Time Frame: Evaluations will be performed every 8 weeks up to 5 years ] [ Designated as safety issue: No ]
    Clinical Benefit is defined as the presence of at least one CR, PR or Stable Disease (SD) (using RECIST v1.0) during treatment

  • Part 2: Time to progression (TTP) [ Time Frame: Evaluations will be performed every 8 weeks up to 5 years ] [ Designated as safety issue: No ]
    Time to progression (TTP) is defined as the time (in months) from the randomization date to the date of progression prior to the start of any subsequent therapy for the primary disease, as reported and documented by the Investigator (i.e. radiological progression per RECIST).

  • Part 2: Overall survival (OS) time [ Time Frame: Evaluations will be performed every 8 weeks up to 5 years ] [ Designated as safety issue: No ]
    Overall survival (OS) time is defined as the time (in months) from randomization to death

  • Part 2: Absorption rate constant (ka) of MSC1936369B [ Time Frame: Days 1, 8, 15, and 22 of Cycle 1 and Days 1, 8 and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Part 2: Clearance from central compartment (CL/f) and intercompartmental clearance (Q/f) of MSC1936369B [ Time Frame: Days 1, 8, 15, and 22 of Cycle 1 and Days 1, 8 and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]
  • Part 2: Volume of central compartment (V1/f) volume of peripheral compartment (V2/f) of MSC1936369B [ Time Frame: Days 1, 8, 15, and 22 of Cycle 1 and Days 1, 8 and 15 of every subsequent cycle up to end of treatment (up to 5 years) ] [ Designated as safety issue: No ]

Enrollment: 141
Study Start Date: November 2009
Estimated Study Completion Date: August 2015
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Safety Run-In (Part 1) Drug: MSC1936369B (MEK Inhibitor)

Two different dosing regimens of MSC1936369B will be tested. QD-5 On/ 2 Off Regimen: MSC1936369B dose escalation treatment will be given orally once daily on Days 1 to 5 and then no medication on Days 6 and 7, that means 5 days on, 2 days off. Patients will continue on Days 8 to 12, 15 to 19 and 22 to 26, and so on up to Day 56 (first cycle) or Day 28 (all other cycles).

BID - Continuous Regimen: MSC1936369B dose escalation treatment will be given orally twice-per-day as continuous daily dosing from Days 1 to 28. There will be no treatment breaks, unless required due to toxicity or adverse events.

Other Name: Pimasertib
Experimental: Part 2 (Gemcitabine + Placebo) Drug: Gemcitabine
Gemcitabine: 1000 mg^m² (milligram per square meter) 30 minutes intravenous infusion on Days 1, 8, 15, 22, 29, 36 and 43 followed by 1 week rest (56-day cycle 1) then on Days 1, 8 and 15 of the following 28-day cycles.
Drug: Placebo
Placebo orally twice daily, continuously without a break for a 28-day cycle (BID continuous Regimen).
Experimental: Part 2 (Gemcitabine + MSC1936369B) Drug: Gemcitabine
Gemcitabine: 1000 mg^m² (milligram per square meter) 30 minutes intravenous infusion on Days 1, 8, 15, 22, 29, 36 and 43 followed by 1 week rest (56-day cycle 1) then on Days 1, 8 and 15 of the following 28-day cycles.
Drug: MSC1936369B (MEK Inhibitor)
MSC1936369B orally, 60 milligram (mg) twice daily, continuously without a break for a 28-day cycle (BID-continuous Regimen).
Other Name: Pimasertib

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
  2. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas and availability of tumor sample.
  3. Evidence of disease (not necessarily measurable disease). Complete tumor assessment including chest X ray, CT scan of abdomen and other scans as necessary to document all sites of disease performed within 28 days prior to trial entry/randomization.
  4. Age ≥ 18 years.
  5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential is defined as: "All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive."
  6. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and four weeks after the last dose of trial medication. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or intrauterine device. The use of hormonal contraceptives should be avoided in female subjects of childbearing potential due to a possible drug-drug interaction.

Exclusion Criteria:

  1. Bone marrow impairment as evidenced by hemoglobin < 9.0 g/dL, neutrophil count < 1.5 x 10^9/L, platelets < 100 x 10^9/L.
  2. Renal impairment as evidenced by serum creatinine > 1.5 x upper limit of normal (ULN), and/or calculated creatinine clearance < 60 mL/min.
  3. Liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN.
  4. Serum calcium > 1 x ULN.
  5. History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases, is stable by CT scan without evidence of cerebral edema, and has no requirements for corticosteroids or anticonvulsants.
  6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
  7. Significant cardiac conduction abnormalities, including QTc prolongation of > 480 ms and/or pacemaker.
  8. Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01016483

Locations
United States, Massachusetts
For Recruiting Locations in the United States, please Contact U.S. Medical Information
Rockland, Massachusetts, United States
Germany
For Recruiting Locations outside the United States, Please contact the Merck KGaA Communication Center
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA
Merck Serono S.A., Geneva
Investigators
Study Director: Lars Damstrup, MD, PhD Merck KGaA
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01016483     History of Changes
Other Study ID Numbers: EMR200066_003, 2009-011992-61
Study First Received: November 18, 2009
Last Updated: August 22, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Belgium: Ministry of Social Affairs, Public Health and the Environment
Belgium: Institutional Review Board
Spain: Comité Ético de Investigación Clínica
Spain: Ministry of Health

Keywords provided by Merck KGaA:
MEK inhibitor
cancer
pancreatic Adenocarcinoma
metastatic
chemo-naive
phase II

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on August 25, 2014