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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study Of Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors

Conditions
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Neoplasms, Malignant Carcinoma

Intervention / Treatment
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* Drug: Neratinib
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic diagnosis of advanced or metastatic solid tumor. Measurable disease per Response Criteria in Solid Tumors (RECIST criteria). Incurable cancer, with disease progression following at least 1 conventional or standard therapy for locally advanced or metastatic disease. Negative pregnancy test for women of child bearing potential. Exclusion Criteria: Chronic treatment with corticosteroids. Primary central nervous system (CNS) tumors and active metastases. Presence of clinically significant or uncontrolled cardiac disease. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom. Symptomatic or prior history of non-infectious interstitial pneumonitis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib and Temsirolimus (Dose level 1)<br>Neratinib 120 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 2)<br>Neratinib 120 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 3)<br>Neratinib 120 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 4)<br>Neratinib 120 mg and Temsirolimus 75 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 5)<br>Neratinib 160 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 6)<br>Neratinib 160 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 7)<br>Neratinib 160 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 8)<br>Neratinib 160 mg and Temsirolimus 75 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 9)<br>Neratinib 200 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 10)<br>Neratinib 200 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 11)<br>Neratinib 200 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|
| Experimental: Neratinib and Temsirolimus (Dose level 12)<br>Neratinib 240 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen | Drug: Neratinib<br> <br> * Other names: HKI-272;Drug: Temsirolimus<br> <br> * Other names: Torisel, CCI-779;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 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. | From first dose date to day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | 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. | 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. | 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. | 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. | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neratinib, solid tumors, phase 1, dose finding study, HKI-272, Nerlynx, Temsirolimus, PB-272