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

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ClinicalTrials.gov Identifier: NCT00838539
Recruitment Status : Completed
First Posted : February 6, 2009
Results First Posted : February 26, 2018
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neoplasms Malignant Carcinoma Drug: Neratinib Drug: Temsirolimus Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study Of Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors
Actual Study Start Date : April 2009
Actual Primary Completion Date : June 2011
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Neratinib and Temsirolimus (Dose level 1)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 2)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 3)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 4)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 5)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 6)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 7)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 8)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 9)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 10)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 11)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779

Experimental: Neratinib and Temsirolimus (Dose level 12)
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
Other Name: HKI-272

Drug: Temsirolimus
Other Name: Torisel, CCI-779




Primary Outcome Measures :
  1. Probability of Dose-Limiting Toxicity (DLT) [ Time Frame: From first dose date to day 28 ]
    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.

  2. Maximum Tolerated Dose (MTD) of Neratinib in Combination With Temsirolimus [ Time Frame: From first dose date to day 28 ]
    Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.

  3. Maximum Tolerated Dose (MTD) of Temsirolimus in Combination With Neratinib [ Time Frame: From first dose date to day 28 ]
    Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib

  4. Adverse Events Causing Dose Limiting Toxicities [ Time Frame: From first dose date to day 21 ]

    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.



Secondary Outcome Measures :
  1. Best Overall Response [ Time Frame: From first dose date to progression/death or last tumor assessment, up to 30 months ]
    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.

  2. Clinical Benefit Rate [ Time Frame: From first dose date to progression/death or last tumor assessment, up to 30 months ]
    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.

  3. Objective Response Rate [ Time Frame: From first dose date to progression/death or last tumor assessment, up to 30 months ]
    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.

  4. Area Under the Curve Tau [ Time Frame: Week 4 ]
    Area Under the Curve tau of neratinib concentrations, collected at 2, 4, 8, and 24 hours post-neratinib administration, at the week 4 dose.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00838539


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
France
Institut Gustave Roussy
Villejuif, France, 94805
Sponsors and Collaborators
Puma Biotechnology, Inc.
Investigators
Study Director: Puma Biotechnology

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier: NCT00838539     History of Changes
Other Study ID Numbers: 3144A1-2205 / B1891016
First Posted: February 6, 2009    Key Record Dates
Results First Posted: February 26, 2018
Last Update Posted: September 18, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:
Neratinib
solid tumors
phase 1
dose finding study
HKI-272
Nerlynx
Temsirolimus
PB-272

Additional relevant MeSH terms:
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents