Study Evaluating Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors

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

Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.

Time frame: From first dose date to day 28

Population: Evaluable subjects were those that either experienced a dose limiting toxicity within the first 28 days, regardless of the number of doses of treatment received, or those that received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment at the original dose level prescribed.

Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib

Time frame: From first dose date to day 28

Population: Evaluable subjects include those that either experienced a dose limiting toxicity within the first 28 days, regardless of the number of doses of treatment received, or those that received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment at the original dose level prescribed.

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

Population: Evaluable subjects for the Maximum Tolerated Dose (MTD) contour estimation were those who either experienced a DLT within the first 28 days, regardless of the number of doses of treatment received, or received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment.

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

Population: Subjects who had pharmacokinetic concentrations available at the dose combination, at day 22.

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

Population: Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (\>= 21 doses of neratinib and \>= 2 doses of temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article\[s\])

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

Population: Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (\>= 21 doses of neratinib and \>= 2 doses of temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article\[s\]).

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

Population: Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (\>= 21 doses of neratinib and \>= 2 doses of Temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article\[s\])