Cabozantinib-S-Malate in Treating Patients With Advanced Solid Tumors and Human Immunodeficiency Virus

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01822522
First received: April 1, 2013
Last updated: July 20, 2016
Last verified: February 2016
  Purpose
This phase I trial studies the side effects and best dose of cabozantinib-s-malate in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment and human immunodeficiency virus. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Advanced Malignant Neoplasm
HIV Infection
Metastatic Malignant Neoplasm
Recurrent Malignant Neoplasm
Solid Neoplasm
Unresectable Malignant Neoplasm
Drug: Cabozantinib S-malate
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons With HIV Infection

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of adverse events reported using the National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • MTD of cabozantinib-s-malate, graded according to the NCI CTCAE version 4.0 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Dose-limiting toxicity (DLT) will be defined as any cabozantinib-s-malate related grade 3 or 4 non-hematologic toxicity including grade 3 nausea and/or vomiting and grade 3 diarrhea despite prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities: thrombocytopenia and neutropenia of any duration (with or without fever or documented infection); additionally, treatment delay of greater than 7 days due to unresolved toxicity or any dose reduction required due to a cabozantinib-related adverse event will be considered a DLT.


Secondary Outcome Measures:
  • CD4+ cell counts [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    A repeated measures analysis of variance will be used to assess the effect of cabozantinib-s-malate on CD4+ cell counts across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, Friedman's test, the nonparametric analogue to a repeated measures analysis of variance, will be used.

  • CD8+ cell counts [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    A repeated measures analysis of variance will be used to assess the effect of cabozantinib-s-malate on CD8+ cell counts across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, Friedman's test, the nonparametric analogue to a repeated measures analysis of variance, will be used.

  • Effects of therapy on HIV viral load [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    A repeated measures analysis of variance will be used to assess the effect of cabozantinib-s-malate on HIV viral loads across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, Friedman's test, the nonparametric analogue to a repeated measures analysis of variance, will be used.

  • Pharmacokinetic parameters [ Time Frame: Days 1, 22, and 23 of course 1 ] [ Designated as safety issue: No ]
    Tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., half life [T½], confidence intervals, and area under the curve) will be compared across relevant antiretroviral therapies using nonparametic statistical testing techniques.

  • Response rates using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1) [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Binomial proportions and their 95% confidence intervals will be used.


Estimated Enrollment: 42
Study Start Date: June 2013
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cabozantinib-s-malate)
Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of cabozantinib (XL184) (cabozantinib-s-malate) as a single agent in solid tumor participants with human immunodeficiency virus (HIV) infection and to determine the maximal tolerated dose (MTD) in this patient population.

SECONDARY OBJECTIVES:

I. To investigate possible pharmacokinetic interactions between cabozantinib and antiretroviral therapy in persons with HIV infection.

II. To investigate the effects of therapy on participant immune status and HIV viral load.

III. To preliminarily assess objective response rates associated with treatment for commonly represented tumors.

OUTLINE: This is a dose-escalation study.

Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must have known HIV infection and histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; any number of prior cancer therapies will be permitted; at least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; prior radiation therapy to the thoracic cavity, abdomen, or pelvis must be completed at least 3 months prior to registration; radiotherapy to any other site (including bone or brain metastases) must be completed at least 28 days prior to registration
  • Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immuno sorbent assay (ELISA), positive western blot, or any other federally approved licensed HIV test; alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and western blot, or other approved diagnostic tests
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin=< 1.5 x upper limit of normal (ULN) (if, however, the participant has Gilbert's disease or unconjugated hyperbilirubinemia that is considered to be secondary to with atazanavir or indinavir therapy, then the total bilirubin must be =< 3 x ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
  • Creatinine =< 1.5 x ULN
  • Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Hemoglobin >= 9 g/dL
  • Serum albumin >= 2.8 g/dL
  • Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
  • Urine protein/creatinine ratio (UPCR) =< 1
  • Serum phosphorus >= lower limit of normal (LLN)
  • Calcium >= LLN
  • Magnesium >= LLN
  • Potassium >= LLN
  • A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within 2 weeks of study participation
  • Women of childbearing potential must have a negative pregnancy test within 7 days before enrollment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of cabozantinib administration; sexually active participants (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 6 months after the last dose of study drug(s), even if oral contraceptives are also used; all participants 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 6 months after the last dose of study drug
  • Participating participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications, when clinically indicated and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 8 weeks following study entry; as study-specific (antiretroviral-based) strata fill, however, only participants who are receiving the therapies eligible for the remaining open strata will be accrued
  • Ability to understand and the willingness to sign a written informed consent document
  • Participants must in the opinion of the investigator be capable of complying with this protocol

Exclusion Criteria:

  • Prior treatment with cabozantinib (XL184)
  • The participant has received radionuclide treatment within 6 weeks of the first dose of study treatment
  • The participant has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 4 weeks or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; note: participants with prostate cancer currently receiving luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents
  • The participant has received any other type of investigational agent within 28 days before the first dose of study treatment
  • The participant has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
  • The participant has a primary brain tumor
  • The participant has active brain metastases or epidural disease; participants with brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; participants with treated brain metastasis should not take enzyme-inducing anticonvulsive therapies (EIACDs) within 2 weeks of registration, though non-enzyme inducing anticonvulsive drugs such as levetiracetam are allowed; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility
  • The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
  • The participant requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor xabans (Xa) inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
  • The participant requires chronic concomitant treatment with the following strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's wort; use of efavirenz or etravirine is permitted for patients considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial; the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
  • The participant requires concomitant treatment with the following inhibitors of CYP3A4:

    • Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin
    • Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole
    • Antidepressants: nefazodone
    • Antidiuretic: conivaptan
    • Gastrointestinal (GI): cimetidine, aprepitant
    • Hepatitis C: boceprevir, telaprevir
    • Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically, ritonavir and cobicistat is permitted for patients considered for the CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial; as part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
  • The participant has 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
  • The participant has radiographic evidence of cavitating pulmonary lesion(s)
  • The participant has tumor invading or encasing any major blood vessels
  • The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders including:

      • Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening
      • Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
      • Any history of congenital long QT syndrome
      • Any of the following within 6 months before the first dose of study treatment:

        • Unstable angina pectoris
        • Clinically-significant cardiac arrhythmias
        • Stroke (including transient ischemic attack [TIA], or other ischemic event)
        • Myocardial infarction
        • Thromboembolic event requiring therapeutic anticoagulation (note: participants with a venous filter [e.g. vena cava filter] are not eligible for this study)
    • Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

      • Any of the following within 28 days before the first dose of study treatment

        • 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 before the first dose of study treatment:

        • Abdominal fistula
        • Gastrointestinal perforation
        • Bowel obstruction or gastric outlet obstruction
        • Intra-abdominal abscess; note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment
  • Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
  • Other clinically significant disorders such as:

    • Active infection requiring systemic treatment within 28 days before the first dose of study treatment; participants with HIV infection will be eligible provided they meet the criteria; participants with known hepatitis B infection should be screened for active disease prior to study participation; participants with known hepatitis C infection must not be actively receiving treatment for the infection
    • Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
    • History of organ transplant
    • Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
    • History of major surgery as follows:

      • 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 months 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
    • In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
  • The participant is unable to swallow tablets that are whole (do not crush or chew or administer via nasogastric [NG]-tube)
  • The participant 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 (ECGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the participant meets eligibility in this regard
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib (XL184)
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cabozantinib
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01822522

Locations
United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
UCLA Center for Clinical AIDS Research and Education Recruiting
Los Angeles, California, United States, 90035
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Ronald T. Mitsuyasu    888-798-0719    rmitsuya@mednet.ucla.edu   
Principal Investigator: Ronald T. Mitsuyasu         
University of California San Diego Recruiting
San Diego, California, United States, 92103
Contact: William Wachsman    858-552-8585 ext 2628    wwachsman@ucsd.edu   
Principal Investigator: William Wachsman         
United States, Hawaii
University of Hawaii Cancer Center Active, not recruiting
Honolulu, Hawaii, United States, 96813
United States, Louisiana
Louisiana State University Recruiting
Lafayette, Louisiana, United States, 70503
Contact: Thomas M. Reske    504-568-2428    emede1@lsuhsc.edu   
Principal Investigator: Thomas M. Reske         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Richard F. Ambinder    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Richard F. Ambinder         
United States, Massachusetts
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Timothy P. Cooley    617-638-8265    timothy.cooley@bmc.org   
Principal Investigator: Timothy P. Cooley         
United States, Missouri
Siteman Cancer Center at Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Lee Ratner    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Lee Ratner         
United States, New York
Montefiore Medical Center-Einstein Campus Withdrawn
Bronx, New York, United States, 10461
Montefiore Medical Center-Weiler Hospital Recruiting
Bronx, New York, United States, 10461
Contact: Missak Haigentz    718-920-4826    mhaigent@montefiore.org   
Principal Investigator: Missak Haigentz         
Montefiore Medical Center - Moses Campus Recruiting
Bronx, New York, United States, 10467-2490
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Robert A. Baiocchi    614-293-3196    Jamesline@osumc.edu   
Principal Investigator: Robert A. Baiocchi         
United States, Texas
Thomas Street Clinic Recruiting
Houston, Texas, United States, 77009
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Elizabeth Y. Chiao    713-794-8666    echiao@bcm.edu   
Principal Investigator: Elizabeth Y. Chiao         
Ben Taub General Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Elizabeth Y. Chiao    713-794-8666    echiao@bcm.edu   
Principal Investigator: Elizabeth Y. Chiao         
United States, Washington
Virginia Mason Medical Center Recruiting
Seattle, Washington, United States, 98101
Contact: David M. Aboulafia    800-354-9527    vmmc.cancer_clinical_research@VirginiaMason.org   
Principal Investigator: David M. Aboulafia         
Harborview Medical Center Recruiting
Seattle, Washington, United States, 98104
Contact: Missak Haigentz       aecc@aecom.yu.edu   
Principal Investigator: Missak Haigentz         
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Corey Casper    800-422-6237    ccasper@fhcrc.org   
Principal Investigator: Corey Casper         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Missak Haigentz AIDS Malignancy Consortium
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01822522     History of Changes
Other Study ID Numbers: NCI-2013-00740  NCI-2013-00740  AMC-087  AMC-087  U01CA121947 
Study First Received: April 1, 2013
Last Updated: July 20, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Infection
Neoplasms
HIV Infections
Acquired Immunodeficiency Syndrome
Neoplasms, Second Primary
Recurrence
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Disease Attributes
Pathologic Processes

ClinicalTrials.gov processed this record on August 29, 2016