Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer

NCT01016483 | Completed Phase 1 Results

• 2 other identifiers: EMR200066_0032009-011992-61
• Study Type: interventional
• Target: 141
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Pancreatic Adenocarcinoma

Keywords

MEK inhibitor; cancer; pancreatic Adenocarcinoma; metastatic; chemo-naive; phase II

Outcome Measures

Primary Outcomes (2)

• Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs)

  DLT using the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) v3.0,was defined as any of the following toxicities at any dose level and judged to be possibly or probably related to trial medication by the Investigator and/or the Sponsor and relevant for the combination treatment: Grade 3/more non-hematological toxicity excluding: Subjects with liver involvement: Grade 4 asymptomatic increases in liver function tests and subject without liver involvement: Grade 3 asymptomatic increases in liver function tests reversible within 7 days. Grade 3 vomiting encountered despite adequate therapy. Grade 3 diarrhea encountered despite adequate anti diarrhea therapy. Grade 4 neutropenia greater (\>) 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia \> 1 day/Grade 3 with bleeding. Grade 4 anemia: Any treatment delay \> 2 weeks due to drug-related adverse effects.

  Up to 28 days in Cycle 1

• Phase II: Progression-Free Survival (PFS) Time

  PFS was defined as the time from randomization to the first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline, Progressive Disease (PD): At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started) or to death due to any cause, whichever occurred first. PFS calculated as (Months) = Date of first PD or death or censoring date minus date of randomization plus 1) divided by 30.4375.

  From the time of randomization to every 8 weeks up to end of treatment (EOT) (6 years)

Secondary Outcomes (27)

• Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation

  From the first dose of study drug administration until EOT (6 years)

• Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1

  0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

• Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

  0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

• Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

  0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

• Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

  0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine

Study Arms (4)

Safety Run-in Part: Regimen 1

EXPERIMENTAL

Subjects will receive pimasertib capsule orally once daily (qd) doses of 15, 30, 45, 68, 90, and 120 milligram (mg) on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Drug: Pimasertib; Drug: Gemcitabine

Safety Run-in Part: Regimen 2

EXPERIMENTAL

Subjects will receive pimasertib capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks) (bid - continuous regimen).

Drug: Pimasertib; Drug: Gemcitabine

Phase II: Arm 1 (Gemcitabine + Placebo)

ACTIVE COMPARATOR

Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo matched to pimasertib orally bid - continuous regimen.

Drug: Gemcitabine; Drug: Placebo

Phase II: Arm 2 (Gemcitabine + Pimasertib)

EXPERIMENTAL

Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib capsule orally bid - continuous regimen.

Drug: Pimasertib; Drug: Gemcitabine

Interventions

Pimasertib DRUG

Also known as: MSC1936369B (MEK Inhibitor)

Phase II: Arm 2 (Gemcitabine + Pimasertib); Safety Run-in Part: Regimen 1; Safety Run-in Part: Regimen 2

Gemcitabine DRUG

Phase II: Arm 1 (Gemcitabine + Placebo); Phase II: Arm 2 (Gemcitabine + Pimasertib); Safety Run-in Part: Regimen 1; Safety Run-in Part: Regimen 2

Placebo DRUG

Phase II: Arm 1 (Gemcitabine + Placebo)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas and availability of tumor sample.
• 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.
• Age ≥ 18 years.
• 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."
• 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.

You may not qualify if:

• Bone marrow impairment as evidenced by hemoglobin less (\<) 9.0 gram per deciliter (g/dL), neutrophil count \< 1.5 x 10\^9/ liter (L), platelets \< 100 x 10\^9/L.
• Renal impairment as evidenced by serum creatinine \> 1.5 x upper limit of normal (ULN), and/or calculated creatinine clearance \< 60 mL/min.
• Liver function abnormality as defined by total bilirubin \> 1.5 x ULN, or aspartate aminotransferase/ alanine aminotransferase (AST/ALT) \> 2.5 x ULN, for subjects with liver involvement AST/ALT \> 5 x ULN.
• Serum calcium \> 1 x ULN.
• 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.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
• Significant cardiac conduction abnormalities, including QT interval corrected for heart rate (QTc) prolongation of \> 480 milliseconds (ms) and/or pacemaker.
• Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.

Sponsors & Collaborators

• EMD Serono: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (2)

For Recruiting Locations in the United States, please Contact U.S. Medical Information

Rockland, Massachusetts, United States

Location

For Recruiting Locations outside the United States, Please contact the Merck KGaA Communication Center

Darmstadt, Germany

Location

Related Publications (1)

• Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, Manojlovic N, Radenkovic D, Verslype C, Raymond E, Cubillo A, Schueler A, Zhao C, Hammel P. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018 Oct 15;143(8):2053-2064. doi: 10.1002/ijc.31603. Epub 2018 Aug 9.

  PMID: 29756206 DERIVED

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis

Interventions

N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; Gemcitabine

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a business of Merck KGaA, Darmstadt, Germany

service@merckgroup.com

+496151725200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2009
• First Posted: November 19, 2009
• Study Start: November 30, 2009
• Primary Completion: December 31, 2013
• Study Completion: April 30, 2015
• Last Updated: July 13, 2017
• Results First Posted: June 23, 2017

Record last verified: 2017-07

Locations

US (1); DE (1)