Clinical trial NCT01378377: Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus
Official title: Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: MEK inhibitor
Temsirolimus
Neoplasms
Phase I
Pimasertib
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2011-06-22
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The research trial is testing the experimental drug pimasertib and the drug Torisel, given together, in the treatment of advanced solid tumors. The primary purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of the drug combination.


Eligibility criteria: Inclusion Criteria:

* Subjects with histologically or cytologically confirmed solid tumors, either refractory to standard therapy or for which no effective standard therapy is available.
* Measurable or evaluable disease at baseline by RECIST 1.0.
* Age \>= 18 years.
* Subject has read and understands the informed consent form and is willing and able to give informed consent.
* Performance Status score of less than or equal to (\<=) 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
* Women of childbearing potential must have a negative blood pregnancy test at the screening visit.
* 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 the trial and for 3 months after the last dose of trial medication.

Additional inclusion criteria also apply.

Exclusion Criteria:

* The subject has previously been treated with mammalian target of rapamycin (mTOR) inhibitor or a mitogen-activated protein kinase (MEK) inhibitor and taken off treatment due to drug-related AEs.
* The subject has received any of the following:
* Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, any investigational agent or any other anti-cancer therapy within 28 days (6 weeks for nitrosoureas or mitomycin C) of Day 1 of trial treatment; non-cytotoxic chemotherapy or investigational agent with limited potential for delayed toxicity is permitted if terminated at least 5 half-lives prior to Day 1 of trial treatment.
* Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation.
* The subject has not recovered from toxicity due to prior therapy to baseline or CTCAE v4.0 of Grade 1 or less (except alopecia).
* The subject has poor organ or marrow function as defined in protocol.
* History of central nervous system (CNS) metastases or primary CNS tumor, unless subject has been previously treated for these conditions, is asymptomatic and has had no requirement for anticonvulsants or high dose corticosteroids for a minimum of 2 weeks prior to entry into the trial.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of Day 1 of trial drug treatment.
* Recent major surgery or trauma (within the last 28 days), unhealing/open wounds, diabetic ulcers, recent drainage of significant volume of ascites or pleural effusion.
* History of congestive heart failure, unstable angina, myocardial infarction, symptomatic cardiac conduction abnormality, pacemaker, or other clinically significant cardiac disease or history of a stroke within 3 months prior to entering the trial.
* Baseline corrected QT interval on screening electrocardiogram (ECG) (QTc) \>= 460 ms or left ventricular ejection fraction (LVEF) \< 40% on screening echocardiogram.
* Other uncontrolled intercurrent diseases
* Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion, or medically relevant abnormal ophthalmology assessments at screening.
* Known or suspected allergy to pimasertib, temsirolimus, other rapamycins (sirolimus, everolimus, etc.), their excipients, or any agent given in the course of this trial.
* Immunization with attenuated live vaccines within one week of trial entry (examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, etc.).
* Concomitant use of any medications or substances that are strong inhibitors or inducers of CYP3A enzyme, including, but not limited to, phenytoin, carbamazepine, barbiturates, azoles, rifampin, phenobarbital, or St. John's Wort.
* Pregnant or lactating female.
* Legal incapacity or limited legal capacity.

Additional exclusion criteria also apply.

Primary outcomes:
measure: Number of Subjects With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 Days (within Cycle 1)
Secondary outcomes:
measure: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From the start of the trial treatment until data cut-off date (23 February 2012)
measure: Maximum Plasma Concentration (Cmax) of Pimasertib
timeFrame: Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Maximum Plasma Concentration (Cmax) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib
timeFrame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib
timeFrame: DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf
measure: Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Apparent Terminal Half-life (t1/2) of Pimasertib
timeFrame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Apparent Terminal Half-life (t1/2) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib
timeFrame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Apparent Volume of Distribution (Vz/F) of Pimasertib
timeFrame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Volume of Distribution (Vz) of Temsirolimus
timeFrame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
measure: Number of Subjects With Disease Control Rate
timeFrame: From the start of the trial treatment until data cut-off date (23 February 2012)
measure: Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Rockland
country: United States
facility: For Recruiting Locations in the US contact US Medical Information in
state: Massachusetts
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: EMD Serono, an affiliate of MerckKGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Mita M, Fu S, Piha-Paul SA, Janku F, Mita A, Natale R, Guo W, Zhao C, Kurzrock R, Naing A. Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. Invest New Drugs. 2017 Oct;35(5):616-626. doi: 10.1007/s10637-017-0442-3. Epub 2017 Feb 13.
citation: Liu X, Lorusso P, Mita M, Piha-Paul S, Hong DS, Fu S, McQuinn L, Asatiani E, Doyle LA, Chen HX, Hess KR, Kurzrock R, Naing A. Incidence of mucositis in patients treated with temsirolimus-based regimens and correlation to treatment response. Oncologist. 2014 Apr;19(4):426-8. doi: 10.1634/theoncologist.2013-0231. Epub 2014 Mar 25.