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NRG-GY007: A phase I/II study of ruxolitinib with front-line neoadjuvant and post-surgical therapy in patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer

Description

This phase I/II partially randomized trial studies the side effects and the best dose of ruxolitinib phosphate when given together with paclitaxel and carboplatin and to see how well they work in treating patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Ruxolitinib phosphate 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 carboplatin, 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 ruxolitinib phosphate together with paclitaxel and carboplatin may be a better treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel and carboplatin alone.

Status

Accepting new patients

Primary Study Objective(s)

The primary objectives of this study are to determine:

  • Incidence of hematologic dose-limiting toxicity (Phase I)

Will be assessed according to Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (CTCAE version 5.0 will be used starting April 1, 2018.

  • Progression-free survival (Phase II)

Will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. A log-rank test utilizing the categorized values of the exploratory laboratory parameters or a Cox proportional hazards (PH) model to estimate of the hazard ratio for progression or death in progression-free-survival. If feasible, the PH model will examine the effect of continuous measures

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including patients who:

  • Have clinically and radiographically suspected and previously untreated International Federation of Gynecologic and Obstetrics (FIGO) stage III or IV epithelial ovarian, primary peritoneal or fallopian tube cancer, high grade, for whom the plan of management will include neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS) who have undergone biopsies for histologic confirmation
  • Note: Institutional confirmation of Mullerian epithelial adenocarcinoma on core biopsy (not cytology or fine needle aspiration) or laparoscopic biopsy; (for phase II of the study formalin-fixed paraffin-embedded [FFPE] tissue should be available for laboratory analysis); patients with any or a combination of the following histologic epithelial cell types are eligible:
    • High-grade serous carcinoma
    • High-grade endometrioid carcinoma
    • Clear cell carcinoma
  • Have measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. (Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI)
  • Have appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 28 days prior to registration
    • Radiographic imaging of the chest, abdomen and pelvis within 28 days prior to registration documenting disease consistent with FIGO stage III or IV disease
  • Have the following:
    • Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0, 1, or 2 within 28 days prior to registration
    • Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl; this ANC cannot have been induced by granulocyte colony stimulating factors (within 14 days prior to registration)
    • Platelets greater than or equal to 100,000/mcl (within 14 days prior to registration)
    • Hemoglobin greater than 9.0 mg/dl (transfusions are permitted to achieve baseline hemoglobin level) (within 14 days prior to registration)
    • Estimated creatinine clearance (CrCl) >= 50 mL/min according to the Cockcroft-Gault formula (within 14 days prior to registration)
    • Bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to registration)
    • Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to registration)
    • Neurologic function: neuropathy (sensory and motor) less than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 1
    • Are able to swallow and retain oral medication
  • Provide study-specific informed consent prior to study entry
  • Submit BRCA testing results (i.e., comprehensive BRCA1 and BRCA2 sequencing, including assessment of gene rearrangements) for enrollment to Amendment 7 and subsequent amendments (Note: BRCA testing results are optional for all patients enrolled prior to Amendment 7. Due to the long acceptance of germline BRCA testing through Myriad, Myriad testing reports will be accepted without additional documentation. If testing for germline BRCA is done by other organizations, in addition to the testing report, documentation from a qualified medical professional, such as ovarian cancer specialty physician involved in the field, high risk genetics physician or genetics counselor,  detailing the laboratory results is required. Please retain a copy of all reports, positive, variants of unknown significance, or negative.)

Excluding patients who:

  • Have suspected non-gynecologic malignancy, such as gastrointestinal
  • Have a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of other malignancy being present within the last three years (two years for breast cancer)
  • Had previous cancer treatment that contraindicates this protocol therapy
  • Had prior chemotherapy for any abdominal or pelvic tumor within the last three years are excluded (Note: Patients may have received prior adjuvant chemotherapy and radiotherapy for localized breast cancer, provided that it was completed more than two years prior to registration, the patient remains free of recurrent or metastatic disease and hormonal therapy has been discontinued)
  • Have received prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic cavity within the last three years are excluded (Note: Prior radiation for localized cancer of the head and neck or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.)
  • Have received any targeted therapy, including but not limited to vaccines, antibodies, tyrosine kinase inhibitors, or hormonal therapy for management of their epithelial ovarian, fallopian tube or peritoneal primary cancer
  • Have mucinous carcinoma, low grade endometrioid carcinoma, low grade serous carcinoma or carcinosarcoma
  • Have synchronous primary endometrial cancer, or a past history of primary endometrial cancer, unless all of the following conditions are met: stage not greater than I-A, grade 1 or 2, no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including serous, clear cell or other FIGO grade 3 lesions
  • Have severe, active co-morbidity defined as follows:
    • Chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment
    • Known brain or central nervous system metastases or history of uncontrolled seizures
    • Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from enrollment, New York Heart Association class III or IV congestive heart failure, and serious arrhythmia requiring medication (this does not include asymptomatic atrial fibrillation with controlled ventricular rate)
    • Partial or complete gastrointestinal obstruction
  • Had major abdominal surgery due to known medical comorbidities
  • Have any condition that in the judgment of the investigator would jeopardize safety or patient compliance with the protocol
  • Are unwilling to be transfused with blood components
  • Are undergoing concurrent anticancer therapy, including  chemotherapy, radiation therapy, biologic therapy, immunotherapy, hormonal therapy, investigational therapy
  • Received an investigational study drug for any indication within 30 days or five half-lives (whichever is longer) prior to day one of protocol therapy
  • Are unable or unlikely to comply with the dosing schedule and study evaluations, in the opinion of the investigator
  • Are pregnant or nursing (Note: the effects of ruxolitinib on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception, such as hormonal, barrier method of birth control or abstinence, prior to study entry and for the duration of study participation and must have a screening negative serum or urine pregnancy test within 14 days of registration. A second pregnancy test must be done within 24 hours prior to the start of the first cycle of study treatment.)
  • Additional notes:
    • Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) do not require contraception
    • Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy and/or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 month amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level greater than 40mIU/mL
  • Have a history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection or known history of tuberculosis; (Note: This exclusion criterion is necessary because the treatments involved in this protocol may be immunosuppressive)
     

Accepting new patients

 

Learn more at

clinicaltrials.gov

 

Principal Investigator(s)

Julian Schink

Justin Chura

Natalie Godbee