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FASN Inhibitor TVB-2640, Paclitaxel, and Trastuzumab in Treating Patients With HER2 Positive Advanced Breast Cancer

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ClinicalTrials.gov Identifier: NCT03179904
Recruitment Status : Recruiting
First Posted : June 7, 2017
Last Update Posted : August 14, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase II trial studies how well FASN inhibitor TVB-2640, paclitaxel, and trastuzumab work in treating patients with HER2 positive breast cancer that has spread to other places in the body. FASN inhibitor TVB-2640 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and trastuzumab, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving FASN inhibitor TVB-2640, paclitaxel, and trastuzumab may work better in treating patients with HER2 positive breast cancer.

Condition or disease Intervention/treatment Phase
HER2 Positive Breast Carcinoma Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Drug: FASN Inhibitor TVB-2640 Other: Laboratory Biomarker Analysis Drug: Paclitaxel Biological: Trastuzumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the overall tumor response rate (ORR i.e. complete response [CR]+partial response [PR]) of the combination of FASN inhibitor TVB-2640 (TVB-2640) with paclitaxel and trastuzumab in patients with taxane and trastuzumab-resistant, advanced HER2-positive breast cancer who have had prior exposure to trastuzumab emtansine (T-DMI) in the metastatic breast cancer setting.

II. To estimate the ORR of the combination of TVB-2640 with paclitaxel and trastuzumab in patients with taxane and trastuzumab-resistant, advanced HER2-positive breast cancer who have not had prior exposure to T-DMI in the metastatic breast cancer setting.

SECONDARY OBJECTIVES:

I. For each patient cohort, to evaluate the safety profile of the combination of TVB-2640 with paclitaxel and trastuzumab.

II. For each patient cohort, to assess the clinical benefit rate (CBR), duration of response, and progression free survival of the combination of TVB-2640 with paclitaxel and trastuzumab.

III. To obtain a point and interval estimate of the difference in RR as well as the difference in CBR between cohort 1 and cohort 2.

TERTIARY OBJECTIVES:

I. For each patient cohort, to assess the changes in FASN, phosphorylation (p)AKT, and pS6 expression in tumor tissue after the first cycle of the combination of TVB-2640 with paclitaxel and trastuzumab from pre-treatment levels.

II. For each patient cohort, to assess the changes in levels of cellular apoptosis in tumor tissue after the first cycle of the combination of TVB-2640 with paclitaxel and trastuzumab from pre-treatment levels.

III. For each patient cohort, to assess the changes in serum FASN after the first cycle of the combination of TVB-2640 with paclitaxel and trastuzumab from pre-treatment levels.

OUTLINE:

Patients receive FASN inhibitor TVB-2640 orally (PO) once daily (QD) on days 1-28, paclitaxel intravenously (IV) over 1-96 hours on days 1, 8, and 15, and trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial to Evaluate the Efficacy of the FASN Inhibitor, TVB-2640, in Combination With Paclitaxel and Trastuzumab in Patients With HER2+ Metastatic Breast Cancer Resistant to Trastuzumab and Taxane-Based Therapy
Actual Study Start Date : August 3, 2017
Estimated Primary Completion Date : July 30, 2021
Estimated Study Completion Date : July 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (FASN inhibitor TVB-2640, paclitaxel, trastuzumab)
Patients receive FASN inhibitor TVB-2640 PO QD on days 1-28, paclitaxel IV over 1-96 hours on days 1, 8, and 15, and trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unexpected toxicity.
Drug: FASN Inhibitor TVB-2640
Given PO
Other Name: TVB-2640

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Biological: Trastuzumab
Given IV
Other Names:
  • ABP 980
  • Anti-c-ERB-2
  • Anti-c-erbB2 Monoclonal Antibody
  • Anti-ERB-2
  • Anti-erbB-2
  • Anti-erbB2 Monoclonal Antibody
  • Anti-HER2/c-erbB2 Monoclonal Antibody
  • Anti-p185-HER2
  • c-erb-2 Monoclonal Antibody
  • HER2 Monoclonal Antibody
  • Herceptin
  • Herceptin Biosimilar PF-05280014
  • Herceptin Trastuzumab Biosimilar PF-05280014
  • MoAb HER2
  • Monoclonal Antibody c-erb-2
  • Monoclonal Antibody HER2
  • PF-05280014
  • rhuMAb HER2
  • RO0452317
  • Trastuzumab Biosimilar ABP 980
  • Trastuzumab Biosimilar PF-05280014




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 3 years ]
    Will be defined as the number of patients whose disease meets the Response Evaluation Criteria in Solid Tumors criteria for a partial or complete response on two consecutive evaluations at least 8 weeks apart divided by the total number of patients in that cohort who started protocol treatment. For each cohort, a two-stage Simon minimax design with a safety run-in period will be used to test the null hypothesis that the true tumor response rate is at most 5% against the alternative it is at least 20%.


Secondary Outcome Measures :
  1. Clinical benefit rate [ Time Frame: Up to 3 years ]
    Will be defined as the proportion of patients who have completed 6 cycles of treatment without disease progression (that is, their objective disease status is a complete response, partial response, or stable for 6 cycles or more). A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival times will be estimated using the Kaplan-Meier approach.

  2. Duration of response [ Time Frame: Up to 3 years ]
    Will be defined as the time from the first radiologic finding of a partial response or complete response to disease progression among those patients whose disease meets the Response Evaluation Criteria in Solid Tumors criteria for complete response or partial response on 2 consecutive evaluations approximately 8 weeks apart. A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival tim

  3. Progression free survival [ Time Frame: Up to 3 years ]
    Will be defined as time from randomization to the first of these disease events: local/regional or distant breast recurrence, ductal breast carcinoma in situ or invasive breast disease in contralateral breast, non-breast second primary, or death due to any cause. A point and interval estimate of the response rate as well as the clinical benefit rate will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. The distribution of response times and progression-free survival times will be estimated using the Kaplan-Meier approach.


Other Outcome Measures:
  1. Changes in biomarker expression [ Time Frame: Baseline up to 28 days ]
    The changes in H score FASN, pAKT, and pS6 expression and levels of cellular apoptosis in tumor tissue. Will be examined graphically by plotting the difference in pre and post levels against pre-levels of the biomarker, with patients who derived clinical benefit represented by dashed line and those who did not by solid line. For each patient cohort, Wilcoxon signed rank tests will be used to assess the changes in serum FASN.



Information from the National Library of Medicine

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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:

  • PRE-REGISTRATION INCLUSION CRITERIA
  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria that is:

    • A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as >= 1.0 cm with computed tomography (CT) scan, CT component of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) and/or
    • A malignant lymph node is considered measurable if its short axis is > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm)
    • Note: tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible
  • Received =< four (4) prior chemotherapy regimens in the metastatic setting
  • One of the following must be true:

    • Progressed on taxane-based chemotherapy in the metastatic setting OR
    • Metastatic disease was diagnosed during or =< 12 months after last dose of neoadjuvant or adjuvant taxane-based chemotherapy
  • One of the following must be true:

    • Progressed on trastuzumab and pertuzumab in the metastatic setting OR
    • Metastatic disease was diagnosed during or =< 6 months after last dose of neoadjuvant or adjuvant HER2-directed therapy
  • Unlimited prior endocrine therapy for hormone receptor positive disease
  • Willingness to provide mandatory tumor tissue specimens for correlative research
  • REGISTRATION INCLUSION CRITERIA
  • Registration must be completed =< 28 days of pre-registration
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Histological confirmation of HER2-positive advanced breast cancer; HER2+ is defined by 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 100,000/mm^3
  • Direct bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement)
  • Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula
  • Cardiac ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% by echocardiogram =< 30 days of registration
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Negative urine pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

    • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of TVB-2640, as follows:

    • For women: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal
    • For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile; men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period
  • Willingness to provide mandatory tumor tissue and/or blood specimens for correlative research

Exclusion Criteria:

  • PRE-REGISTRATION EXCLUSION CRITERIA
  • Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity
  • Patients with a history of LVEF decline to below 50% during or after prior trastuzumab or other HER2 directed therapy
  • Patients with any class of New York Heart Association (NYHA) congestive heart failure (CHF) or heart failure with preserved ejection fraction (HFPEF)
  • Patients with a history of known coronary artery disease or a myocardial infarction within 12 months prior to pre-registration
  • Patients with persistently uncontrolled hypertension (systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical therapy
  • Patients with known unstable angina pectoris
  • Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: controlled atrial fibrillation, paroxysmal supraventricular tachycardia)
  • Patients with a prolonged corrected QT interval (QTc) interval (>= 450 ms)
  • Leptomeningeal disease or uncontrolled brain metastasis

    • NOTE: Metastases treated by surgery and/or radiotherapy such that patient is neurologically stable and off steroids >=12 weeks prior to preregistration are eligible
  • Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

    • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment
  • Tumors involving spinal cord or heart
  • Visceral crisis or lymphangitic spread

    • NOTE: Visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease
  • Uncontrolled intercurrent non-cardiac illness including, but not limited to,

    • Ongoing or active infection
    • Psychiatric illness/social situations
    • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
    • Or any other conditions that would limit compliance with study requirements
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy

    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Prior history of hypersensitivity, drug or radiation-induced, or other immune-mediated pneumonitis
  • Patient is unable to swallow oral medications or has impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome); concomitant therapy with proton pump inhibitors and/or H2-receptor antagonists is permissible
  • Patient has a history of clinically significant dry eye (xerophthalmia) or other corneal abnormality, or if a contact lens wearer, does not agree to abstain from contact lens use from baseline through the last TVB-2640 dose
  • Patients with a history of intolerance to trastuzumab (i.e. a grade 3 or 4 infusion reaction) are excluded; Note: patients with a history of mild infusion reaction to trastuzumab who have previously been successfully re-challenged after an infusion reaction with or without prophylactic medication are allowed
  • Other active malignancy =< 5 years prior to pre-registration

    • EXCEPTIONS: Non-melanoma skin cancer or carcinoma-in-situ of the cervix which has been adequately treated
    • NOTE: If there is a history of prior malignancy, patients must not be receiving other treatment for their cancer and the disease must be inactive/stable
  • REGISTRATION EXCLUSION CRITERIA
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Any of the following therapies prior to registration:

    • Chemotherapy =< 3 weeks
    • Immunotherapy =< 3 weeks
    • Biologic therapy =< 3 weeks
    • Hormonal therapy =< 2 weeks
    • Monoclonal antibodies =< 3 weeks
    • Radiation therapy =< 2 weeks
    • CDK 4/6 inhibitors =< 4 weeks
    • mTOR inhibitors =< 4 weeks

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): NCT03179904


Locations
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United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Donald W. Northfelt         
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Alvaro Moreno-Aspitia         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Tufia C. Haddad         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tufia Haddad Mayo Clinic

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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03179904     History of Changes
Other Study ID Numbers: MC1633
NCI-2017-00944 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1633 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: June 7, 2017    Key Record Dates
Last Update Posted: August 14, 2018
Last Verified: August 2018

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

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Trastuzumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs