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A Study of Debio 1347 Plus Fulvestrant in Patients With Metastatic Breast Cancer

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ClinicalTrials.gov Identifier: NCT03344536
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : October 1, 2019
Sponsor:
Collaborator:
Debiopharm International SA
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of a phase Ib study is to find out the best or maximum tolerated dose of a medication or combination of medications. Therefore, the purpose of this study is to decide the best dose of the study drug, Debio 1347, that can be given in combination with the standard hormonal drug, fulvestrant. Debio 1347 and fulvestrant could shrink the cancer but it could also cause side effects. This study tells us about the side effects of these drugs when given in this new combination, and how often they occur.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Fulvestrant Drug: Debio 1347 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is an open-label, single institution, phase Ib/phase II non-randomized trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of Debio 1347 Plus Fulvestrant in Patients With FGFR-Amplified Endocrine Receptor Positive Metastatic Breast Cancer
Actual Study Start Date : November 10, 2017
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: fulvestrant and Debio 1347
Fulvestrant will be administered according to its approved dose of 500 mg intramuscularly on days 1, 15, 29 and then every 28 days (+/-3 days) thereafter. Debio 1347 will be administered orally daily (1 cycle is 28 days) and the dose of Debio 1347 could be deescalated. The dosage in the phase 2 portion will be the MTD/RP2D determined in the phase 1b portion.
Drug: Fulvestrant
Fulvestrant will be administered according to its approved dose of 500 mg intramuscularly on days 1, 15, 29 and then every 28 days (+/-3 days) thereafter.

Drug: Debio 1347
Debio 1347 will be administered orally daily (1 cycle is 28 days) and the dose of Debio 1347 could be deescalated.




Primary Outcome Measures :
  1. Number of patients experiencing Dose Limiting Toxicity (Phase I) [ Time Frame: 1 year ]
    Selected non-hematologic and hematologic toxicities, as measured by the NCI CTCAE Version 4.0, will be described by frequency and grade, by cycle and over all cycles, with the maximum grade over all cycles used as the summary measure per patient.

  2. proportion of patients who have a best overall response (Phase II) [ Time Frame: 1 year ]
    Tumor response is based on the RECIST v.1.1.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Breast cancer
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and Females Age > 18 years
  • Written informed consent and authorization obtained from the subject/HIPAAappointed legal representative prior to performing any protocol-related procedures including screening evaluations
  • Patients with metastatic histologically or cytologically confirmed invasive breast cancer
  • Female patients of postmenopausal status. with metastatic histologically or cytologically confirmed invasive breast cancer.
  • Postmenopausal status will be defined as following:

    • Age ≥ 60 years
    • Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone and plasma estradiol levels within postmenopausal range by local laboratory assessment in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone (GnRH) agonist or antagonist
    • Prior bilateral oophorectomy
  • Pre or perimenopausal women allowed with the addition of goserelin
  • ECOG performance status 0 -1
  • Tumor must be estrogen receptor and/or progesterone receptor positive ( i.e. Hormone receptor positive (HR+) and HER-2 negative as defined by the ASCO-CAP guidelines: HR+ is defined as expression of ER and/PR in ≥ 1% of cells, or HR+ by local laboratory or regional definition. HER2− is defined as a HER2 IHC score of 0 or 1+ , or an IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification, or a HER2/CEP17 ratio of < 2.0, or local clinical guidelines.
  • Tumors must have FGFR amplifications as determined by a CLIA certified laboratory. Patients with FGFR amplifications co-occurring with 11q amplification (CCND1, FGF3,4, 19 amplifications) are also eligible.
  • Measurable or evaluable disease per RECIST1.1 or pure lytic or mixed lytic-blastic bone lesions
  • No more than 1 prior chemotherapy regimen in the metastatic setting for the phase 2 portion. Patients in the phase 1 portion could have received any number of prior lines of therapy.
  • Willing to undergo a new core or excisional biopsy from a metastatic, not previously irradiated tumor lesion during screening
  • Life expectancy of greater than 3 months
  • Archival Tumor (up to 10 unstained slides) will be obtained, whenever available for additional biomarker analyses
  • Hematologic parameters:

    • White blood cell (WBC) count of > 3000/ul
    • Absolute neutrophil count (ANC) > 1000/ul
    • Platelets > 100,000/ul, hemoglobin > 9.0 g/dl
  • Non-hematologic parameters:

    • Corrected calcium value </= 1.1 x ULN
    • Total bilirubin ≤1.5 x ULN (upper limit of normal) except subject with documented Gilbert‟s syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤3.0 mg/dL
    • AST and ALT ≤ 3 x ULN, unless associated with hepatobiliary metastases, in that case ≤5 x ULN
    • ALP </= 2.5 x ULN or </= 5.0 x ULN for patients with bone metastases
    • Gamma-glutamyltransferase </= 2.5 x ULN
    • Albumin >/= 2.5 g/dL
    • Phosphat </= 1.1 x ULN
    • Prothrombin time (PT) and/or prothrombin time international normalized ratio (PT-INR) and/or activated partial thromboplastin time (APTT) </= 1.3 x ULN
    • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of the

Cockcroft−Gault glomerular filtration rate estimation:

(140 − age) × (weight in kg) × (0.85 if female, 1.0 if male) 72 × (serum creatinine in mg/dL)

  • Patients with "treated and stable" brain lesions for a duration of > 4 weeks may be enrolled.
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication and agree to use effective contraception. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  • Prior Fulvestrant for metastatic breast cancer will be allowed for phase 1 portion but not for the phase 2 portion
  • History of hypersensitivity to any of the excipients in the Debio 1347 formulation (lactose hydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate).
  • Other malignancies requiring active treatment in the last 6 months.
  • Brain tumors and/or brain metastases unless they are asymptomatic, stable on recent imaging (not dated more than 30 days from the inclusion date), and have not required active treatment in the last 6 months.
  • History and/or current evidence of endocrine alteration of calcium-phosphate homeostasis.
  • History of myocardial infarction or stroke within 6 months, congestive heart failure greater than NYHA class II, unstable angina pectoris, unexplained recurrent syncope, cardiac arrhythmia requiring treatment or family history of sudden death from cardiacrelated causes.
  • Baseline Frederica‟s corrected QT (QTcF) interval greater than 470 msec (female) or greater than 450 msec (male), history of congenital long QT syndrome, the presence in the screening ECG of a conduction abnormality that in the opinion of the Investigator would preclude safe participation in this study.
  • Concomitant use of a drug with a known risk of QTc prolongation
  • Current anticoagulation therapy with therapeutic doses of warfarin (low-dose warfarin ≤ 1mg/day or low molecular-weight heparin are permitted).
  • History and or current evidence of ectopic mineralisation/calcification including but not limited to the soft tissue, kidneys, intestine, myocardium and lung with the exception of calcified lymph nodes and asymptomatic coronary calcification.
  • Concomitant use of high dose systemic steroids and other drugs such as calcitonin preparations, active Vitamin D3 preparations, estrogen preparations, selective estrogen receptor modulators, Vitamin K2 preparations, parathyroid hormones, phosphorus absorbers. Note, inhaled, topical steroids and low tapering doses of steroid especially in patients treated recently for brain metastases will be included.
  • Corneal disease, such as bullous or band keratopathy, corneal desquamation, keratitis, corneal ulcer, or keratoconjunctivitis.
  • Known infection requiring the systemic use of, for example, an antibiotic or antiviral agent.
  • Known HIV, HBV or HCV infection.
  • Known untreated or uncontrolled acute infection, including urinary tract infection, within 7 days of study entry.
  • History of organ, bone marrow, or stem cell transplantation.
  • Pregnant or lactating woman (any woman of childbearing potential who has menstruated within the year prior to enrolment will undergo pregnancy testing within 72 hours prior to receiving the first dose of study medication).
  • Women of childbearing potential or men who are unwilling to use an appropriate method of contraception during the study period and for 6 months after completing treatment with Debio 1347. Oral or injectable contraceptive agents cannot be the sole method of contraception. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  • Poorly controlled diabetes mellitus or hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg).
  • Inability or unwillingness to swallow oral medications.
  • Clinically significant gastrointestinal abnormality that would affect the absorption of drug such as gastrointestinal dysfunction, malabsorption syndrome, major resection of the small bowel or total gastrectomy or inflammatory bowel disease.
  • Uncontrolled hydropericardium.
  • Chemotherapy or radiotherapy within 14 days prior to starting study treatment. In case of monoclonal antibodies/biologics, within 28 days prior to starting study treatment.
  • Administration of investigational agents within 28 days prior to treatment initiation.
  • Major surgery and surgery for brain metastases within 28 days prior to screening start. Of note, Intravenous port placement is not considered as a major surgery.
  • Not recovered from AEs or toxicities due to previous treatments to a Grade 1 or less specified in NCI-CTCAE version 4.0 excepting, albumin (< 2.5 g/dL), AST and ALT in patients with liver metastases (> 5 × ULN) ALP in patients with bone metastases (> 5 × ULN) and alopecia.
  • Prior use of a drug targeting FGF or FGFR. Patients previously treated with medications that affect FGFR signaling as a secondary target (e.g., multi-tyrosine kinase inhibitors that primarily inhibit VEGF, but to a lesser extent also affect FGFR signaling) can be considered after discussion with the Principal Investigator.
  • Currently under alcohol or drug abuse rehabilitation or treatment program.
  • Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.

Eligibility Note: Patients could have progressed on prior aromatase inhibitors


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): NCT03344536


Contacts
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Contact: Komal Jhaveri, MD FACP 646-888-5145 jhaverik@mskcc.org
Contact: Sarat Chandarlapaty, MD, PhD 646-888-4311

Locations
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United States, New York
Memorioal Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Komal Jhaveri, MD FACP    646-888-5145      
Contact: Sarat Chandarlapaty, MD, PhD    646-888-4311      
Principal Investigator: Komal Jhaveri, MD FACP         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Debiopharm International SA
Investigators
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Principal Investigator: Komal Jhaveri, MD FACP Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03344536     History of Changes
Other Study ID Numbers: 17-379
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
Debio 1347
Fulvestrant
17-379
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs