MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies

NCT01235897 | Completed Phase 1 Results DMC

• 1 other identifier: 10998
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test the safety and safest highest dose of an investigational drug called MK-2206 when given in combination with paclitaxel and trastuzumab in patients with Human Epidermal growth factor Receptor 2 (HER2)-overexpressing solid tumor malignancies.

Conditions

Advanced Solid Tumors; Tumors; Cancer

Keywords

Neoplasms; Paclitaxel; Trastuzumab

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose of MK-2206 Administered Weekly in Combination With Weekly Paclitaxel 80 mg/m^2 and Trastuzumab 2 mg/m^2

  The MTD was defined as the dose level resulting in 3 or fewer DLTs in 11 patients, per the modified toxicity probability interval (TPI) method (Ji Y, Li Y, Nebiyou Bekele B: Dose-finding in phase I clinical trials based on toxicity probability intervals. Clin Trials 4:235-244, 2007), and confirmed in 4 additional patients. Based on interim toxicity data from other studies, the dose was not escalated beyond 135 mg weekly.

  30 days from initiation of dose

Secondary Outcomes (1)

• Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1

  60 days after dose inititation

Study Arms (1)

Maximum tolerated dose

EXPERIMENTAL

Drug: MK-2206; Drug: Paclitaxel; Drug: Trastuzumab

Interventions

MK-2206 DRUG

Different dose levels of MK-2206 will studied, and co-administered with paclitaxel and trastuzumab. MK-2206 will be given orally with a starting dose of 135 mg weekly

Maximum tolerated dose

Paclitaxel DRUG

80 mg/m2 weekly - paclitaxel

Maximum tolerated dose

Trastuzumab DRUG

2 mg/kg weekly after a 1-time loading dose of 4 mg/kg - trastuzumab

Also known as: Herceptin

Maximum tolerated dose

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically-confirmed metastatic or locally advanced, unresectable HER2+ cancer. HER2+ will be defined as 3+ expression by immunohistochemistry (IHC) OR \>2-fold gene amplification by Fluorescence In Situ Hybridization (FISH).
• Male or female and ≥18 years of age on the day of signing informed consent.
• Performance status of 0-2 on the ECOG Performance Scale and life expectancy \> 3 months.
• Have evaluable disease. Measureable disease is not required
• Adequate organ function as indicated by the following laboratory values:
• Absolute neutrophil count (ANC) = ≥1,500 /μL
• Platelets = ≥100,000 /μL
• Hemoglobin = ≥9 g/dL
• Serum creatinine = ≤1.5 x upper limit of normal (ULN) OR calculated creatinine clearance = ≥60 mL/min for patients with creatinine levels \>1.5 x institutional ULN
• Serum total bilirubin = ≤1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 x ULN
• AST (SGOT) and ALT (SGPT) = ≤2.5 x ULN
• Prothrombin time (PT)/INR = ≤1.2 x ULN
• Partial thromboplastin time (PTT) = ≤1.2 x ULN
• Fasting serum glucose = ≤126 mg/dl
• Hemoglobin A1c (HgbA1c) = ≤7%

You may not qualify if:

• Patient who has had chemotherapy, radiotherapy, or hormonal therapy within 3 weeks (6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from the adverse events due to previous agents administered more than 4 weeks prior to Study Day 1. Patient must not have received trastuzumab or lapatinib within 2 weeks of study Day 1. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.
• Less than 4 weeks post major surgical procedure (defined as one that required general anesthesia)(all surgical wounds must be fully healed).
• Currently participating or has participated in a study with an investigational compound or device within 30 days of Study Day 1.
• Known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids that are used to minimize surrounding brain edema. Patients with clinically insignificant brain metastases that do not require treatment are eligible.
• Has a primary central nervous system tumor.
• Known hypersensitivity to the components of study drug or its analogs.
• History or current evidence of clinically significant heart disease including:
• Left ventricular ejection fraction (LVEF) \<50% on screening echocardiogram or multigated acquisition (MUGA) scan.
• Clinically significant congestive heart failure, unstable angina pectoris,
• Clinically significant cardiac arrhythmia,
• Myocardial infarction during the last 6 months, and/or a current electrocardiogram (ECG) tracing that is abnormal in the opinion of the treating Investigator,
• QTc (QT corrected) prolongation \>450 msec (Bazett's Formula), congenitally long QT syndrome, and/or current anti-arrhythmic therapy, has received any marketed or experimental compound in the last 4 weeks prior to entering the study with possible or known effects of QT prolongation, or cumulative high-dose anthracycline therapy.
• Evidence of clinically significant bradycardia (heart rate \<50), or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV block (Mobitz Type 2), or patients taking beta blockers, non-dihydropyridine calcium channel blockers, or digoxin.
• Uncontrolled hypertension (≥140/90 mmHg). Patients who are controlled on antihypertensive medication will be allowed to enter the study.
• Significant risk for hypokalemia (e.g., patients on high dose diuretics, or with recurrent uncontrolled diarrhea)

Sponsors & Collaborators

• University of California, San Francisco: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94115, United States

Location

MeSH Terms

Conditions

Neoplasms

Interventions

MK 2206; Paclitaxel; Trastuzumab

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

MTD was defined as a dose resulting in 3 or fewer DLTs in 11 patients, plus a cohort of 4 patients by a modified TPI dose escalation method. Based on interim toxicity data from other studies, study dose did not exceed 135mg weekly.

Results Point of Contact

• Title: Jo Chien, MD
• Organization: University of California, San Francisco

crss@ucsf.edu

415-885-7577

Study Officials

• Jo Chien, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2010
• First Posted: November 8, 2010
• Study Start: March 1, 2011
• Primary Completion: March 1, 2013
• Study Completion: November 1, 2013
• Last Updated: April 17, 2014
• Results First Posted: November 19, 2013

Record last verified: 2014-03

Locations

US (1)