Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Trastuzumab

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

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

MK-2206

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

Jo Chien, MD

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.

The purpose of this study is to determine the safety and maximum tolerated dose (MTD) of MK-2206 in combination with paclitaxel and trastuzumab when given to patients with HER2-overexpressing solid tumor malignancies. MK-2206 is an oral drug (taken by mouth) that turns off a protein called AKT inside cancer cells. This could be helpful in treating treatment-resistant cancers, because AKT allows cells to survive despite active anticancer treatment. In the case of HER2-positive cancers, laboratory studies suggest that the drug combination of MK-2206 and paclitaxel and trastuzumab may be effective.

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

A Phase Ib Dose-escalation Trial of the AKT Inhibitor MK2206 in Combination With Weekly Paclitaxel With or Without Trastuzumab

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.

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to qualify for PD, taking as reference the smallest sum diameters while on study

Non-PR/Non-PD: clinical response of chest wall disease not evaluable by RECIST

Merck Sharp & Dohme LLC

University of California, San Francisco

Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks

MK-2206 : MK-2206 given orally at a dose of 135 mg weekly Trastuzumab : 2 mg/kg weekly after a 1-time loading dose of 4 mg/kg - trastuzumab Paclitaxel : 80 mg/m2 weekly - paclitaxel

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

all subjects receiving study treatment were included in study analysis

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.

Sixteen participants completed at least one cycle of therapy and were evaluable for DLT per protocol. Patients were assessed for DLT during the first 4-week cycle.

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

Complete Response (CR)

Partial Response (PR)

Progressive Disease (PD)

Stable Disease (SD)

Non-CR/Non-PD

MK-2206 given orally at a dose of 135 mg weekly + Trastuzumab 2 mg/kg weekly after a 1-time loading dose of 4 mg/kg + Paclitaxel 80 mg/m2 weekly

Analysis included all patients receiving at least 8 weeks of study therapy

Spots Global Cancer Trial Database for MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies

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