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

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.

• Carboplatin (Drug), also known as Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, JM8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo: Given IV
• Paclitaxel (Drug), also known as Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat: Given IV
• Ruxolitinib Phosphate (Drug), also known as INCB-18424 Phosphate, Jakafi, Jakavi: Given PO
• Therapeutic Conventional Surgery (Procedure): Undergo TRS

Primary outcomes

• Dose-limiting Toxicities (Phase I) [42 days (2 cycles)]: 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), or delays in treatment caused by toxicities. A DLT is defined as either hematologic or non-hematologic toxicity (assessed in accordance with the CTEP CTCAE Version 4.0), which cause any of the following (any toxicity): a dose delay > 7 days related to any toxicity, an omission of day 8 or day 15 paclitaxel, any treatment related death. For hematologic toxicity: study treatment-related febrile neutropenia, grade 4 neutropenia lasting > 7 days, study treatment-related grade 4 thrombocytopenia or bleeding associated with grade 3 thrombocytopenia. For non-hematologic toxicity: study treatment related grade 3 or grade 4 non-hematologic toxicity.
• Progression-free Survival (PFS) (Phase II) [The maximum follow-up time for PFS is 57 months.]: 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 PFS. If feasible, the PH model will examine the effect of continuous measures. All patients must have measurable disease, and at least one "target lesion" to be used to assess response as defined by 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

Secondary outcomes

• Number of Participants With Grade 3 or Higher AE (Phase I and II) [Serious and other adverse events were collected from baseline until 30 days after last treatment, an average of 10 months.]: Will be assessed according to CTEP CTCAE version 4.03 (CTCAE version 5.0 will be used starting 04/01/2018). Count of Participants with grade 3 or higher AE. The participants included are the patients in Arm I and the patients in Arm II (DL1 and phase 2). The patients in phase 1 DL2 are not included because they are at a different dose level. The first 17 patients were entered between 11/14/2016 and 10/19/2017. These are the phase 1 patients. Group in DL1 entered 7 patients between 11/14/2016 - 2/17/2017. The DL2 patients were entered between 4/21/2017 and 10/19/2017. There were 10 entered in DL2 because we had a few (3 patients) who were not evaluable and needed to be replaced. From 6/28/2018 to 2/3/2020, we entered the phase 2 patients (42 vs. 88). The first 7 patients were combined with the active therapy on phase 2, for the toxicity comparison (42 vs. 88+7=95 patients).
• 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) [Up to 6 weeks]: Frequencies will be given by the dose-level administered.
• Number of Patients Who Discontinue Ruxolitinib in the First 3 Months of Maintenance Therapy Due to Toxicity (Phase I) [Up to 3 months in the maintenance phase]: Number of patients who discontinue ruxolitinib in the first 3 months of maintenance therapy due to toxicity (Phase I)
• Progression-free Survival (PFS) (Phase II) (Subset Analysis) [From study entry to time of progression or death, whichever occurs first, assessed up to 5 years]: 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.
• Number of Patients Who Have Total Gross Resection (Phase II) [At the time of surgery (surgery occurred within 6 weeks after completion of cycle 3, as soon as nadir counts permit and surgery deemed safe by investigator)]: The outcome is whether there is a total gross resection rate at time of interval cytoreductive surgery among those who had surgery.
• Number of Participants With Complete Pathological Response (Phase II) [At the time of tumor reductive surgery or biopsy after 3 cycles (i.e. after 63 days).]: At the time of TRS, complete pathologic response is defined as no evidence of disease on radiographic imaging at the time of radiographic tumor measurement just prior to TRS, no visible or palpable tumor at the time of surgical exploration, and no pathologic evidence of disease in tissue specimens obtained from TRS.
• Overall Survival (OS) (Phase II) [The average (median) OS follow-up time is 38 months.]: The effect of treatment on OS will be conducted with a Kaplan-Meier analysis and reported as median survival times.

Other outcomes

• Change in Cancer Stem Cells (CSC) Observed in Tissue [Baseline up to 63 days (3 cycles)]: Landmark analyses will be conducted to see if changes in CSC are associated with PFS. The predictive value of CSC will be formally examined with a Cox model using an interaction term with treatment. Subset analyses will be conducted as well in the event that a formal analysis fails to reject the null hypothesis.
• Change in Serum C-reactive Protein (CRP) [Baseline up to 63 days (3 cycles)]: The impact of baseline values on PFS and OS can be assessed for prognostic and predictive significance with log-rank statistics and Cox models. The impact of changes in CRP values on PFS and OS can be examined with landmark analyses or as time dependent covariates.

Sex: Female, ages: 18 Years to any

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)

Participant flow

Outcome results

• Dose-limiting Toxicities (Phase I) (Primary), Number, participants: Phase 1 - DL1 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 2; Phase 1 - DL2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 3
• Progression-free Survival (PFS) (Phase II) (Primary), Median, months: Phase 2 - Arm I (Paclitaxel and Carboplatin) 11.63 (10.32 to 14.39); Phase 2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 14.55 (11.89 to 16.92)
• Number of Participants With Grade 3 or Higher AE (Phase I and II) (Secondary), Count of participants, Participants: Phase 2 - Arm I (Paclitaxel and Carboplatin) 32; Phase 2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 81; Phase 1 - DL1 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 1; Phase 1 - DL2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 3
• 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) (Secondary), Number, participants: Phase 1 - DL1 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 0; Phase 1 - DL2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 3
• Number of Patients Who Discontinue Ruxolitinib in the First 3 Months of Maintenance Therapy Due to Toxicity (Phase I) (Secondary), Number, participants: Phase 1 - DL1 - Arm II (Ruxolitinib, Paclitaxel and Carboplatin) 0; Phase 1 - DL2 - Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 0
• Progression-free Survival (PFS) (Phase II) (Subset Analysis) (Secondary)
• Number of Patients Who Have Total Gross Resection (Phase II) (Secondary), Number, participants: Arm I (Paclitaxel and Carboplatin) 20; Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 49
• Number of Participants With Complete Pathological Response (Phase II) (Secondary), Number, participants: Arm I (Paclitaxel and Carboplatin) 0; Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) 1
• Overall Survival (OS) (Phase II) (Secondary), Median, months: Arm I (Paclitaxel and Carboplatin) 30.8 (24.6 to NA); Arm II (Ruxolitinib, Paclitaxel, and Carboplatin) NA (30.9 to NA)
• Change in Cancer Stem Cells (CSC) Observed in Tissue (Other pre specified)
• Change in Serum C-reactive Protein (CRP) (Other pre specified)

Adverse events

Time frame: Serious and Other Adverse Events were collected from baseline until 30 days after the last treatment, an average of 10 months. All-Cause Mortality was collected from baseline until end of follow-up, an average of 38 months.

Serious adverse events by term

18 more terms not shown.

Other adverse events by term

151 more terms not shown.

10 more sites not listed.

• Results publication: Landen CN, Buckanovich RJ, Sill MW, Mannel RS, Walker JL, DiSilvestro PA, Mathews CA, Mutch DG, Hernandez ML, Martin LP, Bishop E, Gill SE, Gordinier ME, Burger RA, Aghajanian C, Liu JF, Moore KN, Bookman MA. Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study. J Clin Oncol. 2024 Jul 20;42(21):2537-2545. doi: 10.1200/JCO.23.02076. Epub 2024 May 22. PMID 38776484

• Study Protocol and Statistical Analysis Plan (PDF, 2020-02-28)

• Charles N Landen, Principal investigator, NRG Oncology

NIH grants: U10CA180868