The primary purpose of this study is to identify the maximum tolerated dose(s) (MTD) of neratinib in combination with temsirolimus in subjects with solid tumors. This study will also include a preliminary evaluation of efficacy, and assessment of pharmacokinetic (PK) parameters of the combination.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
63
Massachusetts General Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Probability of Dose-Limiting Toxicity (DLT)
A DLT was defined as any dose-limiting Adverse Event related to neratinib + Temsirolimus as Grade 3 or higher nonhematologic toxicity (except neutropenia) or Grade 3 or higher diarrhea lasting \>2 days with optimal antidiarrheal therapy etc.
Time frame: From first dose date to day 28
Maximum Tolerated Dose (MTD) of Neratinib in Combination With Temsirolimus
Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.
Time frame: From first dose date to day 28
Maximum Tolerated Dose (MTD) of Temsirolimus in Combination With Neratinib
Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib
Time frame: From first dose date to day 28
Adverse Events Causing Dose Limiting Toxicities
A DLT was defined as any dose-limiting adverse event (AE) related to neratinib + TEMSR as follows: \[1\] Grade 3 or 4 nonhematologic toxicity (Grade 3 or 4 nausea, vomiting, hyperglycemia, hypophosphatemia, hypertriglyceridemia, or hypercholesterolemia was not considered a DLT unless the subject was already receiving optimal medical therapy). \[2\] Grade 3 or 4 diarrhea lasting \>2 days while subject was on optimal vigorous antidiarrheal therapy. \[3\] Grade 4 neutropenia lasting \>3 days or Grade 3 or 4 neutropenia of any duration with sepsis or a fever \>38.5C. \[4\] Platelet value less than or equal to 25,000/mm3 or bleeding requiring a platelet transfusion. \[5\] Delayed recovery from toxicity, which delayed rescheduled re-treatment for \>3 weeks. \[6\] Inability to maintain the original dose during the first 28 days of treatment (at least 21 doses of neratinib and 2 doses of TEMSR at the original specified dose) due to treatment-related toxicity.
Time frame: From first dose date to day 21
Best Overall Response
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Institut Gustave Roussy
Villejuif, France
The best overall response was described using the data as reported by study center investigators per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose date to progression/death or last tumor assessment, up to 30 months
Clinical Benefit Rate
Percentage of subjects with a complete response, partial response, or stable disease \>= 24 weeks, as determined by investigator assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose date to progression/death or last tumor assessment, up to 30 months
Objective Response Rate
Percentage of subjects with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose date to progression/death or last tumor assessment, up to 30 months
Area Under the Curve Tau
Area Under the Curve tau of neratinib concentrations, collected at 2, 4, 8, and 24 hours post-neratinib administration, at the week 4 dose.
Time frame: Week 4