Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Recurrence

Carcinoma

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.4 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Dose-expansion cohort will enroll patients with advanced breast cancer only after Phase Ib enrollment has been concluded. The MTD of Eribulin mesylate will be administered on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.

Given intravenously (IV)

Phase II: Eribulin mesylate (mg/m2) + Cyclophosphamide (mg/ m2) for advanced breast cancer participants only

Eribulin

Hope S Rugo, MD

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.

This is a phase Ib/II trial designed to determine the maximum tolerated dose (MTD) and does limiting toxicities (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.

Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

A Phase Ib/II Study of Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

Standard dose-confirmation design of 3 to 6 participants per cohort (3+3 design) was used to determine the MTD of eribulin in combination with cyclophosphamide for participants with any solid tumor. The highest dose level or MTD is reached when no more than one of six participants experience a Dose Limiting Toxicity (DLTs). A DLT is defined as any treatment-related toxicity in first 28 days of therapy with a grade 3 or 4 non-hematologic toxicity, a 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. The highest dose level at which no more than one of six participants experience DLT defines the MTD.

The clinical benefit rate is defined as the proportion of participants with confirmed complete response (CR), partial response (PR) and stable disease (SD) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Responses are determined by changes in the largest diameter of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter, PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters, and SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Only participants with measurable disease present at baseline, received at least 1 cycle of therapy, and had disease re-evaluated will be considered evaluable.

Safety of combination of eribulin and cyclophosphamide in participants was assessed by monitoring the frequency of treatment-related toxicities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with an attribute of possibly, probably, or definitely related to treatment. Number of participants by toxicity will be reported.

For the purposes of Phase Ib dose escalation, DLTs will be defined as any treatment-related toxicity occurring within the first 21 days of combination therapy as grade 3 or 4 clinically evident 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.

The ORR is defined as the proportion of participants displaying a CR or PR per RECIST criteria recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response will depend on the achievement of both measurement and confirmation criteria with CR defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter and PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Time to progression will be evaluated as time from first treatment to tumor progression in weeks. Disease progression will be measured 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.

Eisai Inc.

University of California, San Francisco

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Phase 1b: 1.1 mg/m2 Eribulin Combination w/ Cyclophosphamide (Solid Tumor Escalation Cohort)

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.4 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Phase 1b: 1.4 mg/m2 Eribulin Combination w/ Cyclophosphamide (Solid Tumor Escalation Cohort)

Dose-expansion cohort will enroll patients with advanced breast cancer only after Phase Ib enrollment has been concluded. The MTD of Eribulin mesylate will be administered on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Phase II: Eribulin Combination w/ Cyclophosphamide (Breast Cancer Expansion Cohort)

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.1 mg/m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle. The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.4 mg/m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle. The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Total

30-39 years old

40-49 years old

50-59 years old

60-69 years old

70-79 years old

80-89 years old

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Hope Rugo, MD

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Phase 1b: Eribulin Combination w/ Cyclophosphamide (Solid Tumor Escalation Cohort)

Maximum Tolerated Dose (MTD) in Participants With Any Solid Tumor (Phase Ib)

Clinical Benefit Rate for Patients With Advanced Breast Cancer (ABC) (Phase II)

Nausea

Constipation

Fatigue

Peripheral sensory neuropathy

Anorexia

White blood cell decreased

Mucositis oral

Platelet count decreased

Alopecia

Arthralgia

Hemoglobin increased

Headache

Chills

Alanine aminotransferase increased

Rash maculo-papular

Epistaxis

Hypomagnesemia

Edema limbs

Vomiting

Abdominal pain

Anemia

Investigations - Other

Dysgeusia

Alkaline phosphatase increased

Hoarseness

Fever

Neutrophil count decreased

Diarrhea

Hypokalemia

Weight loss

Gastrointestinal disorders - Other

Nasal congestion

Cough

Upper respiratory infection

Sinusitis

Febrile neutropenia

Bone pain

Blurred vision

Peripheral motor neuropathy

Dyspnea

Gastroesophageal reflux disease

Lymphocyte count decreased

Dizziness

Hypoalbuminemia

Hot flashes

Aspartate aminotransferase increased

Memory impairment

Postnasal Drip

Insomnia

Pain

Non-cardiac chest pain

Hypoxia

Portal vein thrombosis

Sepsis

Confusion

Hypophosphatemia

Pain in extremity

Hypercalcemia

Dysphagia

Hyponatremia

Myalgia

Number of Participants With Treatment-related Toxicities

Phase 1b: 1.4 mg/m2 Eribulin Combination w/ Cyclophosphamide (Solid

Number of Participants With Dose Limiting Toxicity (DLT) for Participants With Any Solid Tumor (Phase 1b)

Overall Response Rate (ORR) for Participants With Advanced Breast Cancer (Phase II)

Time to Progression for Participants With Advanced Breast Cancer (Phase II)

Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.4 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD

Eribulin: Given intravenously (IV) Cyclophosphamide: Given IV

Overall Study

Spots Global Cancer Trial Database for unresectable or metastatic carcinoma