Cabozantinib or Paclitaxel in Treating Patients With Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cavity Cancer

• ClinicalTrials.gov Identifier: NCT01716715
• Recruitment Status: Completed
• First Posted: October 30, 2012
• Results First Posted: March 10, 2020
• Last Update Posted: March 10, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 23, 2012
• First Posted Date: October 30, 2012
• Results First Submitted Date: June 26, 2019
• Results First Posted Date: March 10, 2020
• Last Update Posted Date: March 10, 2020
• Actual Study Start Date: November 6, 2012
• Actual Primary Completion Date: March 16, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2020)

Event Free Survival [ Time Frame: The duration of time from study entry to time to progression or death,or begining a subsequent therapy, whichever occurs first, assessed up to 32 weeks ]

Time from patient entry until progression, death, or beginning a subsequent therapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.",

Original Primary Outcome Measures (submitted: October 25, 2012)

PFS [ Time Frame: The duration of time from study entry to time to progression or death, whichever occurs first, assessed up to 7.36 months ]

The data will be examined by a one-sided log-rank test to assess equivalence of equal risks of progressing or dying. The level of significance to be used is 10%.

Current Secondary Outcome Measures (submitted: February 28, 2020)

• Number of Participants With Grade 3 or Higher Adverse Events by Type [ Time Frame: Up to 30 days after completion of study treatment ]
  Toxicities will be characterized by their frequency and severity, grade 3 and above.
• Response, Assessed According to RECIST Version 1.1 [ Time Frame: CT or MRI used to follow lesion every 8 weeks for the first 8 months, then every 12 weeks until disease progression, approximately 2.5 years ]
  Complete and Partial Tumor Response by RECIST. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
• Percentage of Participants With CA125 Response. [ Time Frame: Prior to each cycle of treatment. Then follow-up every 3 months for 2 years then then every 6 months, up to 2.5 years. ]
  Complete and Partial Tumor Response by CA125. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.",
• Overall Survival [ Time Frame: The duration of time from study entry to time of death or the date of last contact, an average of 2.5 years. ]
  The time from randomization until death or date of last contact. Endpoint is death. Patients who are not observed with an endpoint are censored.
• To Estimate the Response Duration Among Patients Who Respond. [ Time Frame: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented or date of death from any cause, whichever came first, assessed up to 18 months. ]
  The time participant is in response.Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.",

Original Secondary Outcome Measures (submitted: October 25, 2012)

• Frequency of adverse events, defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, graded according to the National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
  Toxicities will be characterized by their frequency and severity. Differences in the level of toxicities by treatment regimen will be assessed by classifying them as severe or not severe and examining the relative proportion of severe toxicities.
• Severity of adverse events, defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, graded according to the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
  Toxicities will be characterized by their frequency and severity. Differences in the level of toxicities by treatment regimen will be assessed by classifying them as severe or not severe and examining the relative proportion of severe toxicities.
• Response, assessed according to RECIST version 1.1 [ Time Frame: Up to 5 years ]
• Response, assessed according to CA125 criteria [ Time Frame: Up to 5 years ]
  An examination of response by CA125 (stratified by treatment) will be conducted in those patients who have measurable disease to assess the level of agreement between the two methods of evaluation.
• Overall survival [ Time Frame: The duration of time from study entry to time of death or the date of last contact, assessed up to 5 years ]
  Differences between measurable versus non-measurable disease status will be examined with plots of survival curves, estimates of quartiles and hazard ratios. Formal tests for differences will be carried out with a Cox model or log-rank test if appropriate.
• PFS [ Time Frame: The duration of time from study entry to time of progression or death, whichever occurs first, assessed up to 5 years ]
  Differences between measurable versus non-measurable disease status will be examined with plots of survival curves, estimates of quartiles and hazard ratios. Formal tests for differences will be carried out with a Cox model or log-rank test if appropriate.
• Duration of response (complete response [CR] or partial response [PR]) by treatment [ Time Frame: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years ]

Current Other Pre-specified Outcome Measures (submitted: February 28, 2020)

• c-Met Expression [ Time Frame: Baseline ]
• c-MET Copy Number [ Time Frame: Baseline ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cabozantinib or Paclitaxel in Treating Patients With Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cavity Cancer
• Official Title: A Randomized Phase II Study of NCI Supplied Cabozantinib (NSC #761968) Versus Weekly Paclitaxel (NSC #673089) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
• Brief Summary: This randomized phase II trial studies how well giving cabozantinib-s-malate or paclitaxel works in treating patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cavity cancer. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether cabozantinib-s-malate or paclitaxel is more effective at treating patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cavity cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the activity of cabozantinib (cabozantinib-s-malate) relative to weekly paclitaxel in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer with a log-rank test assessing progression-free survival (PFS) at 3.68 months (approximately pre-cycle 5) and 7.36 months (approximately pre-cycle 9).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE).

II. To estimate and compare the proportion of patients responding to therapy by Response Evaluation Criteria for Solid Tumors (RECIST), cancer antigen 125 (CA125) response, the overall survival (OS), and the duration of response in each arm.

TERTIARY OBJECTIVES:

I. To retrospectively correlate c-met proto-oncogene (MET) expression with overall outcome.

II. To retrospectively correlate c-MET copy number with overall outcome.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Fallopian Tube Carcinoma
• Recurrent Ovarian Carcinoma
• Recurrent Primary Peritoneal Carcinoma

Intervention

• Drug: Cabozantinib S-malate
  Given PO
  Other Names:

  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Study Arms

• Experimental: Arm I (cabozantinib-s-malate)
  Patients receive cabozantinib-s-malate PO QD on days 1-28.
  Interventions:

  • Drug: Cabozantinib S-malate
  • Other: Laboratory Biomarker Analysis
• Experimental: Arm II (paclitaxel)
  Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Drug: Paclitaxel

• Publications *: Matulonis UA, Sill MW, Makker V, Mutch DG, Carlson JW, Darus CJ, Mannel RS, Bender DP, Crane EK, Aghajanian C. A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2019 Mar;152(3):548-553. doi: 10.1016/j.ygyno.2018.12.008. Epub 2018 Dec 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 28, 2020): 111
• Original Estimated Enrollment (submitted: October 25, 2012): 102
• Actual Study Completion Date: February 9, 2019
• Actual Primary Completion Date: March 16, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report

• Patients must have measurable disease or non-measurable (detectable) disease:

  • 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 greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI

  • Non-measurable (detectable) disease is defined in this protocol as the absence of measurable disease but at least one of the following conditions:

    • Ascites and/or pleural effusion attributed to tumor
    • Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
• Patients with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG phase III or rare tumor protocol for the same patient population; in addition, patients must not be eligible for the currently active phase II cytotoxic protocol in platinum resistant disease
• Patients must have a GOG performance status of 0, 1, or 2

• Recovery from effects of recent surgery, radiotherapy, or chemotherapy to baseline or CTCAE =< grade 1 toxicity from all prior therapies except alopecia and other non-clinically significant adverse events (AE's):

  • Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
  • Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to treatment
  • Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted (non-cytotoxic) agents and immunologic agents, must be discontinued at least three weeks prior to treatment
  • Chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor (VEGF) receptor fusion proteins (including VEGF TRAP/aflibercept) must be discontinued for at least 12 weeks prior to treatment
  • Investigational agents must be discontinued for at least 28 days prior to treatment
  • Any prior radiation therapy must be discontinued at least four weeks prior to treatment

• Prior therapy

  • Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) agents (e.g., bevacizumab) or extended therapy administered after surgical or non-surgical assessment; if patients were treated with paclitaxel for their primary disease, this could have been given weekly or every 3 weeks
  • Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen; treatment with weekly paclitaxel for recurrent or persistent disease is NOT allowed
  • Patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy as part of their primary treatment regimen
  • Patients must have NOT received any biologic/targeted (non-cytotoxic) therapy targeting the VEGF and/or MET pathways for management of recurrent or persistent disease
  • For the purposes of this study, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors will be considered "cytotoxic"; patients are allowed to receive, but are not required to receive, PARP inhibitors for management of primary or recurrent/persistent disease (either alone or in combination with cytotoxic chemotherapy); PARP inhibitors will NOT count as a prior regimen when given alone
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
• Platelets greater than or equal to 100,000/mcl
• Hemoglobin greater than or equal to 9 g/dL
• Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.3 x institutional upper limit of normal (ULN)
• Partial thromboplastin time (PTT) less than or equal to 1.3 x ULN
• Creatinine less than or equal to 1.5 x ULN
• Phosphorus, corrected calcium, magnesium and potassium greater than or equal to institutional lower limit of normal (LLN)
• Urine protein creatinine (UPC) ratio must be < 1.0 gm; if UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is recommended
• Bilirubin less than or equal to 1.5 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN
• Alkaline phosphatase less than or equal to 2.5 x ULN
• Albumin greater than or equal to 2.8 g/dL
• Lipase less than or equal to 2 x ULN
• No radiologic or clinical evidence of pancreatitis
• Patients must have a normal baseline thyroid stimulating hormone (TSH); a history of hypothyroidism and/or hyperthyroidism is allowed
• Neuropathy (sensory and motor) less than or equal to grade 1
• Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception; sexually active subjects must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug, even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug; pregnant women are excluded from this study
• Patients must have signed an approved informed consent and authorization permitting the release of personal health information
• Patients must meet pre-entry requirements

Exclusion Criteria:

• Patients who have had previous treatment with cabozantinib; patients who have received previous treatment with weekly paclitaxel for recurrent or persistent disease
• 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; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
• 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 breast, 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 prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
• Uncontrolled hypertension, defined as systolic greater than 140 mm Hg or diastolic greater than 90 mm Hg despite antihypertensive medications
• Myocardial infarction or unstable angina within 6 months prior to registration
• New York Heart Association (NYHA) class II or greater congestive heart failure
• History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic atrial fibrillation with controlled ventricular rate
• Any history of congenital long QT syndrome
• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization; note: if initial QTcF is found to be > 500 ms, two additional electrocardiogram (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
• Patients with serious non-healing wound, ulcer, or bone fracture within 28 days before treatment
• Patients with history of organ transplant
• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving (in contact with, invading or encasing) major vessels

• Patients who have experienced any of the following:

  • Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  • Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• Patients who have radiographic evidence of cavitating pulmonary lesion(s)
• Patients who have tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before treatment

• Gastrointestinal disorders, particularly those with potential risk of perforation or fistula formation including:

  • Any of the following within 28 days of registration

    • Intra-abdominal tumor/metastases invading GI mucosa
    • Active peptic ulcer disease
    • Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    • Malabsorption syndrome

  • Any of the following within 6 months of registration

    • Abdominal fistula
    • Gastrointestinal perforation
    • Bowel obstruction or gastric outlet obstruction; note: patients requiring drainage gastrostomy (e.g., percutaneous endoscopic gastrostomy [PEG] tube) and/or parenteral hydration and/or nutrition are not eligible
    • Intra-abdominal abscess; note: complete resolution of an intra-abdominal abscess must be confirmed prior to registration even if the abscess occurred more than 6 months prior to registration
• Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures which are not controlled with non-enzyme inducing anticonvulsants, any brain metastases and/or epidural disease, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of study treatment
• The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)
• Patients who are unable or unwilling to swallow tablets
• Patients who are pregnant or nursing
• The subject requires concomitant treatment, in therapeutic doses, with anti-coagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors or antiplatelet agents (i.e. clopidogrel); low dose aspirin (=< 81 mg/day) low-dose warfarin (=< 1 mg/day) and prophylactic low molecular weight heparin are permitted
• Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications
• Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications
• Patients with concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01716715
• Other Study ID Numbers: NCI-2012-02058; NCI-2012-02058 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); GOG-0186K; S13-00312; GOG-0186K ( Other Identifier: NRG Oncology ); GOG-0186K ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract ); U10CA027469 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ursula A Matulonis; NRG Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: February 2020