E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced breast carcinoma in patients with trastuzumab-refractory HER2-amplified disease |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer which has grown in spite of standard treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072737 |
E.1.2 | Term | Advanced breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1
To determine the maximum tolerated dose (MTD) of weekly intravenous (IV) temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy.
Phase 2
• To estimate the efficacy [overall response rate (ORR) = complete response (CR) and partial response (PR)] by RECIST (v 1.1) of temsirolimus when administered in combination with neratinib at the established maximum tolerated dose (MTD) for both HER2-amplified trastuzumab-refractory and triple-negative patients.
• To estimate the ORR for patients with dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients.
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E.2.2 | Secondary objectives of the trial |
Phase 1:
• To determine if the addition of neratinib affects the exposure and half-life of temsirolimus and its active metabolite, sirolimus.
Phase 2 :
• To determine the safety and tolerability of temsirolimus when administered in combination with neratinib.
• To determine progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR, i.e., CR + PR + SD ≥24) weeks for the combination at the MDT, and overall survival (OS).
• To assess the safety of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients.
Exploratory:
• Exploratory end points are detailed in the protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Phase 1 HER2-Amplified (HER2-Positive) Cohort – Closed to accrual
Phase 2 HER2-Amplified (HER2-Positive) Cohort - US only (Not EU)
Phase 1 Triple-Negative Cohort – Closed to accrual
Phase 2 Triple-Negative Cohort – Closed to accrual
Phase 2 HER2-Positive Cohort with dose escalation
• HER2 overexpression and/or amplification as determined by IHC (3+) or FISH (≥2.0).
• Previously received trastuzumab as part of a regimen in the adjuvant or metastatic setting with evidence of progression. Washout period for trastuzumab of 14 days.
• May have previously received lapatinib as part of a regimen in the adjuvant or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
• Radiographic progression of disease while on treatment with trastuzumab as defined by RECIST 1.1 criteria.
• Prior therapy inclusion:
o No restriction on prior chemotherapy regimens for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.
Inclusion Criteria for ALL patients
• Patients with a diagnosis of invasive adenocarcinoma of the breast confirmed by histology or cytology.
• Metastatic disease that is or has been pathologically documented.
• At least one measurable metastatic lesion according to RECIST 1.1 criteria. Ascites, pleural effusions, and bone metastases are not considered measurable. Minimum indicator lesion size ≥10 mm by helical computerized tomography (CT) or ≥20 mm by conventional techniques.
o Pathological nodes must be ≥15 mm by the short axis to be considered measurable.
• Age ≥18, as no dosing or adverse event data are currently available on the use of neratinib or temsirolimus in patients <18 years of age.
• Patients must be willing to discontinue sex hormonal therapy, e.g., birth control pills, hormonal replacement therapy, prior to enrollment. Women of childbearing potential must consent to use effective contraception while on treatment and for 28 days thereafter. Men must consent to use a barrier method of contraception while on treatment and for 3 months thereafter.
• Negative serum human chorionic gonadotropin (HCG) pregnancy test for premenopausal women of reproductive capacity and for women less than 12 months after menopause.
• Asymptomatic, central nervous system metastases are permitted if patients remain clinically stable after discontinuation of steroids and anticonvulsants for 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
• Patients must have normal organ and marrow function: AST/ALT ≤2.5x institutional upper limit of normal except for patients with liver metastases. For patients with liver metastases, AST/ALT/alkaline phosphatase ≤5.0 x institutional upper limit of normal. Total bilirubin within institutional limits except for patients with liver metastases. For patients with liver metastases, total bilirubin ≤1.5x institutional upper limit of normal. Creatinine clearance within normal limits or ≥60 mL/min, prothrombin time (PT) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5x institutional upper limit of normal except for patients on Coumadin or low molecular weight heparin, leukocytes ≥3,000/µL, absolute neutrophil count ≥1,000/µL, and platelets ≥75,000/µL.
• Able to swallow and retain oral medication.
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E.4 | Principal exclusion criteria |
• Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating breast cancer.
• Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P glycoprotein (P gp) substrates ≤30 days prior to initiation of investigational products.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or temsirolimus.
• Women who are pregnant or breast feeding.
• Life expectancy <3 months.
• Completion of previous chemotherapy regimen <3 weeks prior to the start of study treatment. Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy with bevacizumab for the treatment of metastatic disease must be discontinued ≥3 weeks from the start of protocol treatment.
• Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but might be allowed for pre-existing non-target lesions with approval from the Sponsor.
• Concurrent medical conditions which may increase the risk of toxicity, including ongoing or active infection, history of significant bleeding disorder unrelated to cancer (congenital bleeding disorders, acquired bleeding disorders within one year), human immunodeficiency virus (HIV)-positive or active hepatitis.
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, and left ventricular ejection fraction less than 50% measured by a multigated acquisition imaging (MUGA scan) of the heart or an echocardiogram (ECHO).
• QTc interval >0.47 seconds.
• Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, or uncontrolled inflammatory GI disease.
• History of an invasive second primary malignancy diagnosed within the previous 3 years, except for stage I endometrial or cervical carcinoma or prostate carcinoma treated surgically, and non-melanoma skin cancer.
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
• Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures are necessary to participation in this clinical trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in the Phase 2 portion of the trial is the ORR (CR + PR) by RECIST 1.1.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients are evaluable for response if they complete at least one week of treatment.
Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include:
• PFS
• DoR
• CBR (CR + PR + SD ≥24 weeks)
• OS
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
to identify a maximum tolerated dose |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
open-label, single arm, adaptive design, dose-escalation Phase 1/2 study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Hong Kong |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival). In the event that the EOS is declared earlier patients who continue to receive clinical benefit from neratinib plus temsirolimus will be offered the opportunity to continue to receive this combination via a treatment extension study or expanded access protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |