Neratinib and Capmatinib Combination (Phase Ib/II) in Metastatic Breast Cancer and Inflammatory Breast Cancer Patients With Abnormal HER-family and c-Met Pathway Activity as Measured by the CELsignia Signaling Analysis Test

Study Overview
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Brief Summary
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This study is to learn if the combination therapy of capmatinib and neritinib can help to control metastatic or locally advanced breast cancer. Researchers also want to find the highest tolerable dose of the combination therapy of capmatinib and neritinib that can be used in this study drug combinations. The safety of this drug combination and the CELsignia MP test methodology will also be studied.

Detailed Description
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This is an open-label, phase Ib/II study of neratinib plus Capmatinib in patients with metastatic breast cancer and metastatic IBC. Phase 1b - Dose Escalation of Neratinib with Capmatinib This phase of the study will employ the Bayesian optimal interval (BOIN) design with the 3+3 design run-in, to find the MTD. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM). The maximum sample size for dose escalation is 27. Patients are treated in cohorts of 3, beginning with Neratinib PO dose level 1 (120 mg, Days 1-7, 160 mg, through end of treatment, see Table 2) in combination with Capmatinib PO level 1 (400 mg, see Table 3), with a maximum of 12 patients per dose. The target toxicity rate for the maximum tolerable dose (MTD) is 25%. Phase II Phase II will be a prospective, open label, interventional study with previously treated HER2-negative metastatic breast cancer and metastatic inflammatory breast cancer patients. Subjects receive Capmatinib in combination with neratinib. The MTD determined during Phase 1b will be used. This portion of the trial will be conducted to assess the overall response rate (ORR) for patients treated at the MTD. The target ORR will be 25%, with unacceptable ORR as 5%. We assess the ORR using the Bayesian optimal phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017). Up to an additional 29 evaluable subjects with measurable disease will be enrolled. An interim analysis will be performed when the number of enrolled patients reaches 15.

Official Title
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Neratinib and Capmatinib Combination (Phase Ib/II) in Metastatic Breast Cancer and Inflammatory Breast Cancer Patients With Abnormal HER-family and c-Met Pathway Activity as Measured by the CELsignia Signaling Analysis Test

Conditions
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Metastatic Breast Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Neratinib
* Drug: Capmatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Signed Informed Consent Form (ICF) and comply with the requirements of the study protocol Age 18 years ECOG performance status 0-1 Confirmed diagnosis of metastatic breast cancer or inflammatory breast cancer according to international consensus criteria30: Onset: Rapid onset of breast erythema, edema, and/or peau d'orange, and/or warm breast, with or without an underlying breast mass Duration: History of such findings no more than 6 months Extent: Erythema occupying at least 1/3 of whole breast Pathology: Pathologic confirmation of invasive carcinoma Patients with metastatic or recurrent IBC which is not amenable to curative treatment with available local and systemic therapy or metastatic non-IBC after 1-6 lines of therapies for metastatic disease with at least 2 weeks washout period before the initiation of study treatment. For Phase Ib, any ER, PR, and HER2 status, For Phase 2, HER2-negative per ASCO/CAP guidelines and any ER and PR status. For Phase II only, Patients with measurable disease according to the Response Evaluation Criteria in Solid Tumor (RECIST, v1.1) (local or distant) and at least one metastatic lesion amendable for biopsy (core or punch) Left Ventricular Ejection Fraction ≥ 50% measured by MUGA scan or Echocardiogram. Abnormal HER-family and c-Met signaling activity based on CELsignia MP Test results (for phase II patients only). Participants must have adequate organ function including the following laboratory values at the screening visit. Screening must occur within 28 days prior to the first dose of study drug. Screening samples for hematology and serum chemistries must be drawn within 14 days prior to the first dose of study drug Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without growth factor support Platelets (PLT) >= 75 x 10^9/L Hemoglobin (Hgb) >= 9 g/dL ( Calculated creatinine clearance (using Cockcroft-Gault formula) >= 45 mL/min Total bilirubin (TBIL) =< ULN (upper limit of normal) with the following exception: Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled Aspartate transaminase (AST) =< 3 x ULN, except for participants with liver metastasis, who may only be included if AST =< 5 x ULN Alanine transaminase (ALT) =< 3 x ULN, except for participants with liver metastasis, who may only be included if ALT =< 5 x ULN Alkaline phosphatase (ALP) =< 5.0 x ULN Asymptomatic serum amylase =< grade 2. Participants with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.) Serum lipase =< ULN Willing and able to comply with scheduled visits, treatment plan and laboratory tests Exclusion Criteria: Concurrent anticancer therapy within 2 weeks of initiation of study treatment; except: Unstable and symptomatic brain metastasis (Stable disease is defined as CNS radiographic study 4 weeks from completion of radiotherapy and 2 weeks from discontinuation of corticosteroids) Adverse events from prior anticancer therapy that have not resolved to Grade 1 (CTCAE v 5.0) except for alopecia, vitiligo, pain, constipation, diarrhea, or fatigue if these symptoms existed during screening baseline. i. Grade 3 or above neuropathy induced from prior treatment, that is not resolved to grade 2 or below despite best supportive care Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis Acute exacerbations of underlying condition within the last 12 months (requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids) Patients with known HIV infection: 1) CD4+ count<350 cells/uL; or 2) had AIDS-defining opportunistic infections < 12 months Know active hepatitis B (chronic or acute) or hepatitis C infection: Severe infections within 4 weeks prior to study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia Signs or symptoms of infection within 2 weeks prior to study treatment per treating physician and PI judgement. Concurrent oral or IV antibiotics within 5 days prior to study treatment * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are allowed and eligible so long as the antibiotic is not prohibited with the study medication (See Tables 8 and 10). Major surgical procedure within 28 days prior to study treatment or anticipation of need for a major surgical procedure during the course of the study Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention). Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome Clinically significant, uncontrolled heart diseases. Unstable angina within 6 months prior to screening Myocardial infarction within 6 months prior to screening History of documented congestive heart failure (New York Heart Association functional classification III-IV) Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening Ventricular arrhythmias Supraventricular and nodal arrhythmias not controlled with medication Other cardiac arrhythmia not controlled with medication QTcF (QT interval corrected by Fridericia's formula) ≥ 470 ms on the screening ECG (as mean of triplicate ECG) Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting study therapy or who have not recovered from side effects of such procedure. Unable to swallow or absorb study drugs due to impairment of GI function or GI disease e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome Participants receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of capmatinib, and for the duration of the study. Other severe, acute, or chronic medical or psychotic conditions, substance abuse or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results Pregnant or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for one month after stopping treatment. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject Use of injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Sexually active males will not be eligible unless they use a condom during intercourse while taking drug and for 3 months after stopping treatment and should not father a child in this period. A condom is required for all sexually active male to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to partner. In addition, male participants must not donate sperm for the time period specified above Participants receiving treatment with the following medications that cannot be discontinued at least 1 week prior to the start of treatment with study therapy and for the duration of the study:

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1b (dose escalation)<br>This portion of the study will enroll a maximum of 27 patients in the dose-finding trial including the possibility of adding up to 6 additional ER+ patients in a safety assessment of aromatic inhibitor treatment | Drug: Neratinib<br>* Nertatinib will be supplied as 40 mg tablets, equivalent to 48.31 mg neratinib maleate.<br>Drug: Capmatinib<br>* Capmatinib will be supplied at 200 mg and 150 mg tablets<br>|
| Experimental: Part 2 (dose expansion)<br>This portion of the study will enroll a maximum of 29 patients | Drug: Neratinib<br>* Nertatinib will be supplied as 40 mg tablets, equivalent to 48.31 mg neratinib maleate.<br>Drug: Capmatinib<br>* Capmatinib will be supplied at 200 mg and 150 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine maximum tolerated dose for use in the Phase II portion of the trial |  | through study completion, an average of 1 year | 
| To determine overall response rate (ORR: CR+PR) |  | through study completion, an average of 1 year |