Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by University of California, San Francisco
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01554371
First received: March 9, 2012
Last updated: August 15, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to test the safety of eribulin (Halaven™) and cyclophosphamide (Cytoxan®) given together at different doses. This study will look at what effects, good and/or bad, that these drugs have on solid tumors. Eribulin is a drug that has been approved by the FDA for breast cancer that has spread to other parts of the body. Cyclophosphamide has been approved for different types of cancers (including breast cancer). However, the combination of eribulin and cyclophosphamide is considered experimental; that means this combination has not been approved by the FDA.

The funding for this study is provided by Eisai Inc., the maker of eribulin.


Condition Intervention Phase
Malignant Solid Tumour
Breast Cancer Nos Metastatic Recurrent
Neuropathy
Drug: Eribulin in Combination w/ Cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Phase Ib: 1. Maximum tolerated dose (MTD) of eribulin in combination with cyclophosphamide in patients with any solid tumor [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]

    Standard dose-confirmation design: 3 to 6 patients per cohort (3+3 design), 9-18 total patients with any solid tumor malignancy

    • DLTs reviewed to determine dose escalation to the next highest level
    • Highest dose level: no more than one of six subjects experience DLT defines the MTD
    • DLT defined as any treatment-related toxicity in first 28 days of therapy: grade 3 or 4 non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia lasting >7 days or febrile neutropenia; or any clinically significant toxicity grade 2 or higher that requires more than 14 days to resolve

  • Phase II 1. Clinical benefit (complete response, partial response, and stable disease) of the combination of eribulin and cyclophosphamide in patients with advanced breast cancer [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: No ]

    Patients will be re-evaluated for response at 6 weeks (after 2 cycles), then every 9 weeks until end of study therapy. Confirmatory scans will not be performed since this is a Phase I/II trial and the primary endpoints are safety, toxicity, and clinical benefit rate.

    Response and progression will be evaluated in this study using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria



Secondary Outcome Measures:
  • Phase Ib: 1. Safety of treatment [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]

    Evaluate safety of treatment with the combination of eribulin and cyclophosphamide in patients with any solid tumor.

    Toxicities will be graded for management according to NCI-CTCAE version 4.0. Eribulin and cyclophosphamide dose-modification guidelines are outlined the full protocol. Both agents should be held for all instances of febrile neutropenia (ANC < 1000/μL). GCSF (Filgrastim) or Pegylated-GCSF (Neulasta) growth factor support is encouraged for ANC < 1500/ μL and may be used at the discretion of the treating physician EXCEPT during the day 1-6 of the first cycle.


  • Phase Ib: 2. Dose Limiting Toxicity (DLT) [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]
    AE and toxicity assessments done on Day 1 of every Cycle. DLT is defined as any treatment-related toxicity in first 28 days of therapy.

  • Phase Ib: 3. Pharmacokinetics (PK) and potential for drug-drug interaction [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]

    Relationships between combination of eribulin/cyclophosphamide pharmacodynamic, pharmacogenomic and response prediction biomarkers

    • Single-nucleotide polymorphism variations evaluating potential toxicities including peripheral neuropathy, bone marrow suppression
    • DNA extraction and analysis for 3 novel candidate genes which may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5
    • Circulating tumor cell analysis
    • Evaluate archival tumor specimens for exploratory markers of target validation and response, mutational analyses (correlate w/ CTC studies results)

  • Phase Ib: 4. Quality of life [ Time Frame: Study duration (up to 24 months) + 10 yrs or survival follow-up ] [ Designated as safety issue: No ]
    Evaluate quality of life endpoints: assessment tools EORTC QLQ-C30 (6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination), FACT/GOG-Ntx & 10-point Modified Neuropathy Score

  • Phase Ib: 5. Pharmacodynamic, pharmacogenomic and response prediction biomarkers [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]

    Explore relationships between combination of eribulin/cyclophosphamide pharmacodynamic, pharmacogenomic and response prediction biomarkers

    • Single-nucleotide polymorphism variations evaluating potential toxicities including peripheral neuropathy, bone marrow suppression
    • DNA extraction and analysis for 3 novel candidate genes which may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5
    • Circulating tumor cell analysis
    • Evaluate archival tumor specimens for exploratory markers of target validation and response, mutational analyses (correlate w/ CTC studies results)

  • Phase II 1. Efficacy of drug combination in patients with advanced breast cancer including response rate, duration of response and time to progression [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: No ]

    Patients are re-evaluated for response at 6 weeks (after 2 cycles), then every 6 9 weeks until end of study therapy. Confirmatory scans will not be performed since this is a Phase I/II trial and the primary endpoints are safety, toxicity, and clinical benefit rate.

    Response and progression will be evaluated usingResponse Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria.


  • Phase II 2. Safety of drug combination in expanded cohort - metastatic breast cancer [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]
    AE and toxicity assessments done Day 1 of every Cycle. Toxicities graded for management according to NCI-CTCAE version 4.0. Eribulin and cyclophosphamide dose-modification guidelines outlined in full protocol. Both agents should be held for all instances of febrile neutropenia (ANC < 1000/μL). GCSF or Pegylated-GCSF growth factor support is encouraged for ANC < 1500/ μL and may be used at the discretion of the treating physician EXCEPT during the day 1-6 of the first cycle.

  • Phase II 3. Quality of life endpoints [ Time Frame: Study duration (up to 24 months) + 10 years or survival follow-up ] [ Designated as safety issue: No ]
    Evaluate quality of life endpoints: assessment tools EORTC QLQ-C30 (6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination), FACT/GOG-Ntx & 10-point Modified Neuropathy Score

  • Phase II 4. Pharmacodynamic, pharmacogenomic and response prediction biomarkers [ Time Frame: Estimated up to 24 months ] [ Designated as safety issue: Yes ]

    Explore relationships between combination of eribulin/cyclophosphamide pharmacodynamic, pharmacogenomic and response prediction biomarkers

    • Single-nucleotide polymorphism variations evaluating potential toxicities including peripheral neuropathy, bone marrow suppression
    • DNA extraction and analysis for 3 novel candidate genes which may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5
    • Circulating tumor cell analysis
    • Evaluate archival tumor specimens for exploratory markers of target validation and response, mutational analyses (correlate w/ CTC studies results)


Estimated Enrollment: 58
Study Start Date: March 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eribulin Combination w/ Cyclophosphamide
Phase Ib: dose escalation; Phase II: advanced breast cancer patients
Drug: Eribulin in Combination w/ Cyclophosphamide

Phase Ib Eribulin mesylate (mg/m2)

Level -1: 0.7 day 1, 8

Level 0 (start): 1.1 day 1, 8

Level 1: 1.4 day 1, 8

Cyclophosphamide (mg/ m2) Level -1: 600 day 1

Level 0: 600 day 1

Level 1: 600 day 1

Phase II The dose-expansion will enroll 40 patients with advanced breast cancer


Detailed Description:

This is a phase Ib/II trial designed to determine the MTD and DLTs of the combination of eribulin and cyclophosphamide in solid tumors and make preliminary estimates regarding efficacy of this treatment in patients with advanced breast cancer.

The study includes a standard dose-confirmation schema (phase Ib portion) enrolling 3 to 6 patients/subjects, with any solid tumors, per cohort (3+3 design) with a total of 18 patients. The dose-expansion (phase II portion) will enroll 40 patients with advanced breast cancer to detect an effect size of 15% with a power of 80% with endpoints of safety, efficacy, and clinical benefit rate. A maximum of 58 patients will be enrolled on the phase Ib and II portions of this trial combined and will be treated until disease progression or toxicity mandate treatment change.

Eribulin is a non-taxane microtubule inhibitor that is FDA approved as monotherapy for the treatment of taxane and anthracycline resistant metastatic breast cancer. The combination of docetaxel and cyclophosphamide is a well-accepted adjuvant chemotherapy regimen that has become an increasingly common therapeutic choice for intermediate risk early stage breast cancer. Eribulin has a favorable toxicity profile compared to docetaxel with the most common adverse reactions (incidence ≤25%) including neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. Eribulin appears to have activity in taxane resistant disease, making it an attractive partner with cyclophosphamide.

Neuropathy can be a devastating complication from adjuvant chemotherapy and in the metastatic setting, may limit effective therapy and reduce quality of life. Understanding the host factors that predict risk for neuropathy is critical, as these patients may in particular benefit from the lower risk of neuropathy associated with eribulin therapy. In conjunction with this trial, we have included correlative studies to study the proposed pharmacogenomic factors associated with risk of neuropathy. In this way we will potentially be able to identify patients who could preferentially be treated with less neurotoxic microtubule inhibitors.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION

  1. Phase Ib: Patient must have histologically or cytologically documented solid tumor malignancies.

    Phase II: Patients must have histologically or cytologically confirmed locally advanced, unresectable or metastatic carcinoma of the breast.

  2. Patient is male or female and ≥18 years of age on the day of signing informed consent.
  3. Patient must have performance status of 0-2 on the ECOG Performance Scale and life expectancy > 3 months.
  4. Patient must have evaluable disease. Measureable disease is not required
  5. Patient must have adequate organ function
  6. Female patient of childbearing potential must have a negative serum or urine pregnancy test β-hCG within 72 hours prior to receiving the first dose of study medication and agree to the use of effective methods of contraception while on study.
  7. Any number of prior lines of chemotherapy in the metastatic setting is allowed.
  8. Concomitant use of bisphosphonates is allowed.
  9. Patients with stable and clinically insignificant CNS disease are allowed. Patients must be off steroids with no new CNS symptoms or findings on radiographic imaging for 1 month.
  10. Patients willing and able to complete the questionnaires.
  11. Patients willing and able to comply with the study protocol for the duration of the study.
  12. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.

EXCLUSION

  1. Patients who have had chemotherapy or radiotherapy within two weeks, 4 weeks for nitrosoureas, mitomycin C, pegylated-doxorubicin and one half-life for bevacizumab, hormone therapy within one week, trastuzumab within 2 weeks or lapatinib within one week of study Day 1.
  2. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.
  3. Patients with non-healing surgical wounds. Patients must be at least two weeks from a major surgical procedure, and surgical wounds must be completely healed.
  4. Patients with known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as:

    1. no evidence of new or enlarging CNS metastasis
    2. off steroids that are used to minimize surrounding brain edema. Patients with clinically insignificant brain metastases that do not require treatment are eligible.
  5. Patients with known hypersensitivity to the components of study drug or its analogs.
  6. Significant cardiovascular impairment:

    1. Congestive heart failure, Clinically significant cardiac arrhythmia, history or current evidence of a myocardial infarction during the last 6 months, and/or a current ECG tracing that is abnormal in the opinion of the treating Investigator, or unstable angina
    2. QTc prolongation >480 msec (Bazett's Formula) or congenitally long QT syndrome
  7. Severe/uncontrolled concurrent illness/infection
  8. Patients with other active, current primary malignancies, other than carcinoma in situ of the cervix or non-melanoma skin cancer
  9. Patients with > Grade 1 neuropathy at screening
  10. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative
  11. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
  12. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01554371

Contacts
Contact: Hope S Rugo, MD hrugo@medicine.ucsf.edu

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94143
Principal Investigator: Hope S Rugo, MD         
Principal Investigator: Amy P Moore, MD         
Sub-Investigator: Pamela N Munster, MD         
Sub-Investigator: John W Park, MD         
Sub-Investigator: Mark JM Magbanua, phD         
Sub-Investigator: Leslie Floren, PhD         
Sub-Investigator: Deanna Kroetz, PhD         
Sub-Investigator: Michelle Melisko, MD         
Sub-Investigator: Mark Moasser, MD         
Sub-Investigator: Andrei Goga, MD         
Sponsors and Collaborators
University of California, San Francisco
Eisai Inc.
Investigators
Principal Investigator: Hope Rugo, MD University of California, San Francisco
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01554371     History of Changes
Other Study ID Numbers: UCSF Protocol Number11996
Study First Received: March 9, 2012
Last Updated: August 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
Solid tumor
Metastatic breast cancer
Unresectable or metastatic carcinoma
Neuropathy
Eribulin
Cyclophosphamide

Additional relevant MeSH terms:
Neoplasms
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on October 16, 2014