Trial Outcomes & Findings for MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies (NCT NCT01235897)

Last Updated: 2014-04-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

17 participants

Primary outcome timeframe

30 days from initiation of dose

Results posted on

2014-04-17

Participant Flow

Patients were enrolled on the study between April 2011 and January 2013. This is a phase one study; the number enrolled was guided by ongoing toxicity assessment.

17 patients were initially enrolled; however, one participant experienced rapid progression of disease before receiving any study treatment.

Participant milestones

Participant milestones
Measure	MK-2206 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
Overall Study STARTED	16
Overall Study COMPLETED	16
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MK-2206 n=16 Participants 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	52 years n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants
Region of Enrollment United States	16 participants n=5 Participants

PRIMARY outcome

Timeframe: 30 days from initiation of dose

Population: 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.

Outcome measures

Outcome measures
Measure	MK-2206 n=16 Participants 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
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	135 mg

SECONDARY outcome

Timeframe: 60 days after dose inititation

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

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

Outcome measures

Outcome measures
Measure	MK-2206 n=16 Participants 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
Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1 Complete Response (CR)	3 participants
Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1 Partial Response (PR)	7 participants
Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1 Progressive Disease (PD)	1 participants
Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1 Stable Disease (SD)	4 participants
Best Disease Response by Response Evaluation Criteria in Solid Tumor (RECIST), Version 1.1 Non-CR/Non-PD	1 participants

Adverse Events

MK-2206

Serious events: 5 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	MK-2206 n=17 participants at risk 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
Hepatobiliary disorders Liver dysfunction	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Hemorrhage	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Death	17.6% 3/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Nervous system disorders Pain - neuralgia	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Pain - Abdominal	5.9% 1/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Infection with rash grade 3 ANC	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks

Other adverse events

Other adverse events
Measure	MK-2206 n=17 participants at risk 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
Blood and lymphatic system disorders Anemia	52.9% 9/17 • Number of events 14 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Neutropenia	82.4% 14/17 • Number of events 30 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Hyperglycemia	100.0% 17/17 • Number of events 31 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Skin and subcutaneous tissue disorders Rash	88.2% 15/17 • Number of events 24 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Fatigue	64.7% 11/17 • Number of events 19 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Anorexia/weight loss	70.6% 12/17 • Number of events 15 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Diarrhea	64.7% 11/17 • Number of events 18 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Nausea	35.3% 6/17 • Number of events 6 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Psychiatric disorders Depression	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Constipation	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Dehydration	11.8% 2/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Xerostomia	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Intermittent GERD pain	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Dyspepsia	17.6% 3/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Hemorrhoid	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Hepatobiliary disorders Elevated ALT	41.2% 7/17 • Number of events 7 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Hepatobiliary disorders Elevated AST	52.9% 9/17 • Number of events 16 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Hypoalbumenia	11.8% 2/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Hepatobiliary disorders Hyperbilirubin	23.5% 4/17 • Number of events 8 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Hypercalcemia	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Renal and urinary disorders Elevated Creatinine	5.9% 1/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Renal and urinary disorders Hemoglobinuria	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Renal and urinary disorders Proteinuria	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Lower extremity weakness	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Psychiatric disorders Anxiety	11.8% 2/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Peripheral Neuropathy	58.8% 10/17 • Number of events 19 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Stomatitis	35.3% 6/17 • Number of events 8 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Altered Taste	17.6% 3/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Vomiting	11.8% 2/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Epistaxis	29.4% 5/17 • Number of events 8 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Hepatobiliary disorders Hypobilirubin	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Infections and infestations Infection	11.8% 2/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Eye disorders Eye swelling	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Respiratory, thoracic and mediastinal disorders Rhinorrhea	23.5% 4/17 • Number of events 4 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased Hematocrit	94.1% 16/17 • Number of events 19 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased lymphocytes	11.8% 2/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased monocytes	11.8% 2/17 • Number of events 3 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased RBC	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased WBC	41.2% 7/17 • Number of events 16 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased Hemoglobin	47.1% 8/17 • Number of events 15 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased platelets	23.5% 4/17 • Number of events 7 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Insomnia	23.5% 4/17 • Number of events 4 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Skin and subcutaneous tissue disorders Cracks to fingertips	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Skin and subcutaneous tissue disorders Alopecia	58.8% 10/17 • Number of events 11 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Skin and subcutaneous tissue disorders Nail changes	17.6% 3/17 • Number of events 6 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Arthralgia	17.6% 3/17 • Number of events 4 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Headache	11.8% 2/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Respiratory, thoracic and mediastinal disorders Sinus Pain	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Myalgia	11.8% 2/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Musculoskeletal and connective tissue disorders Left Calf Pain	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased Potassium	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased Magnesium	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Decreased Calcium	5.9% 1/17 • Number of events 2 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Blood and lymphatic system disorders Elevated BUN	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Gastrointestinal disorders Abdominal pain	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Groin pain	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
General disorders Cough	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Respiratory, thoracic and mediastinal disorders Dyspnea	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Renal and urinary disorders Cystitis	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks
Renal and urinary disorders Urinary retention	5.9% 1/17 • Number of events 1 • 40 weeks Toxicity assessment continued as long as patient received study treatment; the longest on-study duration was 40 weeks

Additional Information

Jo Chien, MD

University of California, San Francisco

Phone: 415-885-7577

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place