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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 September 2014 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: September 16, 2014
Last verified: September 2014
  Purpose

This phase I trial studies the side effects and best dose of cabozantinib-s-malate in treating patients with advanced solid tumors 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
HIV Infection
Unspecified Adult Solid Tumor, Protocol Specific
Drug: cabozantinib-s-malate
Other: pharmacological study
Other: laboratory biomarker analysis
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:
  • 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 ]
  • Maximal tolerated dose (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, neutropenia of more than 5 days duration, and neutropenia of any duration with fever or documented infection; additionally, treatment delay of 14 days or greater due to unresolved toxicity or any dose reduction required due to a cabozantinib-related adverse event will be considered a DLT.


Secondary Outcome Measures:
  • Response rates using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 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

  • 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 CD4+ cell counts and HIV viral loads across time points.

  • 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 and HIV viral loads across time points.

  • 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 [Cl], and area under the curve [AUC]) will be compared across relevant antiretroviral therapies using nonparametic statistical testing techniques.


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
  • Cometriq
  • XL184
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
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 patients 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 patient 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
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients 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 × upper limit of normal (ULN) (for subjects with Gilbert's disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia [without aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation], =< 3 × ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 × institutional upper limit of normal
  • Creatinine =< 1.5 × 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 × 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 at screening; 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 subjects (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 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 6 months after the last dose of study drug
  • Participating patients 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; patients 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 patients 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
  • Subjects must in the opinion of the investigator be capable of complying with this protocol

Exclusion Criteria:

  • Prior treatment with cabozantinib (XL184)
  • The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment
  • The subject 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: Subjects with prostate cancer currently receiving luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents
  • The subject has received any other type of investigational agent within 28 days before the first dose of study treatment
  • The subject 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 subject has a primary brain tumor
  • The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects 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; subjects 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 subjects with known brain metastases is required to confirm eligibility
  • The subject 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 subject 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 subject requires chronic concomitant treatment with the following strong cytochrome P450 3A4 (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 subject 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
  • The subject 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 subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor in contact with, invading or encasing any major blood vessels
  • The subject 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: subjects 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; patients with HIV infection will be eligible provided they meet the criteria; patients with known hepatitis B infection should be screened for active disease prior to study participation
    • 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 subject is unable to swallow tablets that are whole (do not crush or chew or administer via nasogastric [NG]-tube)
  • 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 (ECGs) 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
  • 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, New York
Albert Einstein College of Medicine Recruiting
Bronx, New York, United States, 10461
Contact: Missak Haigentz    718-920-4826    mhaigent@montefiore.org   
Principal Investigator: Missak Haigentz         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Elizabeth Y. Chiao    713-794-8666    echiao@bcm.edu   
Principal Investigator: Elizabeth Y. Chiao         
Sponsors and Collaborators
Investigators
Principal Investigator: Missak Haigentz AIDS Associated Malignancies Clinical Trials Consortium
  More Information

No publications provided

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: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Communicable Diseases
Infection
Neoplasms
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases

ClinicalTrials.gov processed this record on November 20, 2014