Clinical Trials /

Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT02713386

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.

Related Conditions:
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal Clear Cell Carcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NRG-GY007
  • SECONDARY ID: NCI-2016-00203
  • SECONDARY ID: NRG-GY007
  • SECONDARY ID: NRG-GY007
  • SECONDARY ID: NRG-GY007
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02713386

Conditions

  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • FIGO Stage III Ovarian Cancer
  • FIGO Stage IIIA Ovarian Cancer
  • FIGO Stage IIIA1 Ovarian Cancer
  • FIGO Stage IIIA2 Ovarian Cancer
  • FIGO Stage IIIB Ovarian Cancer
  • FIGO Stage IIIC Ovarian Cancer
  • FIGO Stage IVA Ovarian Cancer
  • FIGO Stage IVB Ovarian Cancer
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Stage III Fallopian Tube Cancer AJCC v7
  • Stage III Primary Peritoneal Cancer AJCC v7
  • Stage IIIA Fallopian Tube Cancer AJCC v7
  • Stage IIIA Primary Peritoneal Cancer AJCC v7
  • Stage IIIB Fallopian Tube Cancer AJCC v7
  • Stage IIIB Primary Peritoneal Cancer AJCC v7
  • Stage IIIC Fallopian Tube Cancer AJCC v7
  • Stage IIIC Primary Peritoneal Cancer AJCC v7
  • Stage IV Fallopian Tube Cancer AJCC v6 and v7
  • Stage IV Primary Peritoneal Cancer AJCC v7

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (paclitaxel and carboplatin)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (paclitaxel and carboplatin)
RuxolitinibINCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424Arm II (ruxolitinib, paclitaxel, and carboplatin)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiArm II (ruxolitinib, paclitaxel, and carboplatin)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine whether treatment with ruxolitinib phosphate (ruxolitinib) in combination with
      conventional neoadjuvant and post-surgical chemotherapy is safe and tolerable in the primary
      therapy for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. (Phase I)
      II. Demonstrate whether treatment with ruxolitinib in combination with conventional
      neoadjuvant and post-surgical chemotherapy results in a prolonged progression-free survival
      when compared to chemotherapy alone, in primary therapy for epithelial ovarian, fallopian
      tube, or primary peritoneal carcinoma. (Phase II)

      SECONDARY OBJECTIVES:

      I. Determine frequency of patients who do not receive surgery within 6 weeks of completing
      cycle 3 therapy for reasons other than non-response, disease progression, or medical
      contraindications. (Phase I) II. Determine if continuation of ruxolitinib as maintenance
      therapy in participants who complete 6 cycles of standard chemotherapy in combination with
      ruxolitinib and have not experienced unacceptable toxicity or disease progression is safe and
      tolerable. (Phase I) III. Determine the impact of ruxolitinib in combination with
      chemotherapy on progression-free survival as a function of proposed exploratory biomarkers -
      ALDH+ CD133+ (possibly also CD24+ CK19+) co-staining by AQUA immunofluorescence (IF); ratio
      of tumor expression of CD8:FOXP3 by immunohistochemistry (IHC); and tumor CD3, CD4, TAI-1,
      HLA class I and II, CD68 expression by IHC in archived tumor tissue, BRCA status, and serum
      C-reactive protein (CRP) and IL-6 levels in pre-treatment serum. (Phase II) IV. Investigate
      the prognostic significance of exploratory laboratory parameters in terms of both
      progression-free survival and overall survival in women receiving conventional chemotherapy
      alone. (Phase II) V. Determine whether treatment with ruxolitinib in combination with
      conventional chemotherapy is associated with total gross resection rate at time of interval
      cytoreductive surgery. (Phase II) VI. Determine whether treatment with ruxolitinib in
      combination with conventional chemotherapy is associated with complete pathologic response
      defined at interval cytoreductive surgery. (Phase II) VII. Demonstrate whether treatment with
      ruxolitinib in combination with conventional chemotherapy results in an improvement in
      overall survival in primary management of epithelial ovarian, fallopian tube, or primary
      peritoneal carcinoma. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of ruxolitinib phosphate, followed by a
      phase II study.

      PHASE I PORTION OF STUDY IS COMPLETE (04/06/2018)

      PHASE I (CYCLES 1-3): Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on
      days 1-21, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV
      over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of
      disease progression or unacceptable toxicity. Within 6 weeks after completion of cycle 3,
      patients undergo tumor reductive surgery (TRS).

      PHASE I (CYCLES 4-6): Within 6 weeks of TRS, patients receive ruxolitinib phosphate PO BID on
      days 1-21, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes
      on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression
      or unacceptable toxicity. If TRS is not performed due to non-response or medical
      contraindications and criteria for discontinuation of protocol therapy have not been met,
      patients should resume ruxolitinib phosphate, paclitaxel, and carboplatin within 6 weeks of
      completing cycle 3 of therapy.

      MAINTENANCE THERAPY: Within 3 weeks after completion of cycle 6, patients receive ruxolitinib
      phosphate PO BID. Treatment continues in the absence of disease progression or unacceptable
      toxicity.

      PHASE II: Patients are randomized to 1 of 2 treatment arms.

      ARM I (CYCLES 1-3): Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and
      carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the
      absence of disease progression or unacceptable toxicity. Within 6 weeks after completion of
      cycle 3, patients undergo TRS.

      ARM I (CYCLES 4-6): Within 4 weeks of surgery (or within 6 weeks of completion of cycle 3 in
      patients who do not undergo TRS), patients receive paclitaxel IV over 1 hour on days 1, 8,
      and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3
      cycles in the absence of disease progression or unacceptable toxicity.

      ARM II (CYCLES 1-3): Patients receive ruxolitinib phosphate PO BID on days 1-21 and
      paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 cycles in the
      absence of disease progression or unacceptable toxicity. Within 6 weeks after completion of
      cycle 3, patients undergo TRS.

      ARM II (CYCLES 4-6): Within 4 weeks of surgery (or within 6 weeks of completion of cycle 3 in
      patients who do not undergo TRS), patients receive ruxolitinib phosphate PO BID on days 1-21
      and paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 cycles in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients in phase I are followed up until resolution of
      adverse events, and patients in phase II are followed up every 3 months for 2 years and then
      every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (paclitaxel and carboplatin)Active ComparatorSee Detailed Description.
  • Carboplatin
  • Paclitaxel
Arm II (ruxolitinib, paclitaxel, and carboplatin)ExperimentalSee Detailed Description.
  • Carboplatin
  • Paclitaxel
  • Ruxolitinib
  • Ruxolitinib Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must 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

          -  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 the following histologic epithelial cell types are eligible:
             high grade serous carcinoma, high grade endometrioid carcinoma, clear cell carcinoma,
             or a combination of these

          -  All patients must 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

          -  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

               -  Further protocol-specific assessments

          -  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

          -  Ability to swallow and retain oral medication

          -  The patient must provide study-specific informed consent prior to study entry

          -  BRCA testing results (i.e., comprehensive BRCA1 and BRCA2 sequencing, including
             assessment of gene rearrangements) must be submitted for all patients enrolled to
             Amendment 7 and subsequent amendments; 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
             (e.g., ovarian cancer specialty physician involved in the field, high risk genetics
             physician, genetics counselor) detailing the laboratory results is required; please
             retain a copy of all reports (positive, variants of unknown significance [VUS], or
             negative)

        Exclusion Criteria:

          -  Patients with suspected non-gynecologic malignancy, such as gastrointestinal

          -  Patients with 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 (2 years for
             breast cancer); patients are also excluded if their previous cancer treatment
             contraindicates this protocol therapy

          -  Patients who have received prior chemotherapy for any abdominal or pelvic tumor within
             the last three years are excluded; patients may have received prior adjuvant
             chemotherapy and radiotherapy for localized breast cancer, provided that it was
             completed more than 2 years prior to registration, the patient remains free of
             recurrent or metastatic disease and hormonal therapy has been discontinued

          -  Patients who have received prior radiotherapy to any portion of the abdominal cavity
             or pelvis or thoracic cavity within the last three years are excluded; 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

          -  Patients who 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

          -  Patients with mucinous carcinoma, low grade endometrioid carcinoma, low grade serous
             carcinoma or carcinosarcoma

          -  Patients with 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

          -  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

          -  Patients who are not candidates for major abdominal surgery due to known medical
             comorbidities

          -  Patients with any condition that in the judgment of the investigator would jeopardize
             safety or patient compliance with the protocol

          -  Patients who are unwilling to be transfused with blood components

          -  Concurrent anticancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy,
             immunotherapy, hormonal therapy, investigational therapy)

          -  Receipt of an investigational study drug for any indication within 30 days or 5
             half-lives (whichever is longer) prior to day 1 of protocol therapy

          -  Patients who, in the opinion of the investigator, are unable or unlikely to comply
             with the dosing schedule and study evaluations

          -  Patients who are pregnant or nursing; the effects of ruxolitinib on the developing
             human fetus are unknown; for this reason, women of child-bearing potential (WOCBP)
             must agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation; WOCBP
             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; women must not be breastfeeding

               -  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

          -  Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
             infection or known history of tuberculosis; (This exclusion criterion is necessary
             because the treatments involved in this protocol may be immunosuppressive)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of hematologic (heme) dose-limiting toxicity (Phase I)
Time Frame:42 days (2 cycles)
Safety Issue:
Description: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 04/01/2018).

Secondary Outcome Measures

Measure:Incidence of adverse events (Phase I)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed according to CTEP CTCAE version 4.03 (CTCAE version 5.0 will be used starting 04/01/2018).
Measure:Frequency of patients who could not receive surgery within the defined timeframe for reasons other than non-response, disease progression, or medical contraindications (Phase I)
Time Frame:Up to 6 weeks
Safety Issue:
Description:Frequencies will be given by the dose-level administered.
Measure:Number of patients who discontinue ruxolitinib in the first 3 months of maintenance therapy due to toxicity (Phase I)
Time Frame:Up to 3 months in the maintenance phase
Safety Issue:
Description:
Measure:Progression-free survival (PFS) (Phase II)
Time Frame:From study entry to time of progression or death, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Will be assessed according to RECIST 1.1. Subset analyses within categorized, important exploratory laboratory parameters will examine the treatment effect on PFS. The effect of treatment on PFS will be examined within each of these subsets using a log-rank test or a Cox PH model. Interest will center on whether the hazard of PFS changes from one group to another. The impact of the biomarkers on PFS will be assessed using log-rank tests or Cox PH models.
Measure:Proportion of patients who have total gross resection (Phase II)
Time Frame:At the time of surgery
Safety Issue:
Description:Will be defined as no visible or palpable tumor remaining after completion of surgery. Differences in the proportion who have total gross resection by treatment arm will be examined with Fisher?s Exact Test. The results of this analysis will be presented in terms of the odds ratio (maximum-likelihood estimations and confidence intervals). Multivariate logistic modeling will be conducted if feasible.
Measure:Complete pathological response (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as no evidence of disease on radiographic imaging at the time of radiographic tumor measurement. Differences in the proportion who have complete pathological response by treatment arm will be examined with Fisher?s Exact Test. Multivariate logistic modeling will be conducted if feasible.
Measure:Overall survival (OS) (Phase II)
Time Frame:From randomization until death or date last seen, assessed up to 5 years
Safety Issue:
Description:The effect of treatment on OS will be conducted with the log-rank statistic and characterized with a Cox PH model. The impact of the biomarkers on OS will be assessed using log-rank tests or Cox PH models.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

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