Clinical Trials /

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

NCT01822522

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib S-Malate in Treating Patients With Advanced Solid Tumors and Human Immunodeficiency Virus
  • Official Title: Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons With HIV Infection

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-00740
  • SECONDARY ID: NCI-2013-00740
  • SECONDARY ID: AMC-087
  • SECONDARY ID: AMC-087
  • SECONDARY ID: AMC-087
  • SECONDARY ID: U01CA121947
  • SECONDARY ID: UM1CA121947
  • NCT ID: NCT01822522

Conditions

  • Advanced Malignant Solid Neoplasm
  • HIV Infection
  • Metastatic Malignant Solid Neoplasm
  • Recurrent Malignant Solid Neoplasm
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib s-malate)

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.

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. Cycles
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib s-malate)ExperimentalPatients receive cabozantinib s-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib S-malate

Eligibility 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 immunosorbent 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 (within 1 week of study entry)

          -  Absolute neutrophil count >= 1,500/mcL (within 1 week of study entry)

          -  Platelets >= 100,000/mcL (within 1 week of study entry)

          -  Total bilirubin=< 1.5 x upper limit of normal (ULN) (within 1 week of study entry)
             (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 (within 1 week of study entry)

          -  Creatinine =< 1.5 x ULN (within 1 week of study entry)

          -  Creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels
             above institutional normal (within 1 week of study entry)

          -  Hemoglobin >= 9 g/dL (within 1 week of study entry)

          -  Serum albumin >= 2.8 g/dL (within 1 week of study entry)

          -  Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis (within 1
             week of study entry)

          -  Urine protein/creatinine ratio (UPCR) =< 1 (within 1 week of study entry)

          -  Serum phosphorus >= lower limit of normal (LLN) (within 1 week of study entry)

          -  Calcium >= LLN (within 1 week of study entry)

          -  Magnesium >= LLN (within 1 week of study entry)

          -  Potassium >= LLN (within 1 week of study entry)

          -  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

          -  The effects of cabozantinib on the developing human fetus are unknown; for this reason
             and because tyrosine kinase inhibitors agents as well as other therapeutic agents used
             in this trial are known to be teratogenic, 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 participants considered for the CYP3A4-inducer based antiretroviral
             therapy (ART) regimen arm (Stratum B) of the trial; because the lists of CYP3A4
             inducers are constantly changing, it is important to regularly consult a
             frequently-updated list; medical reference texts such as the Physicians' Desk
             Reference may also provide this information; 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 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 participants considered for the
                  CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial; because the
                  lists of CYP3A4 inhibitors are constantly changing, it is important to regularly
                  consult a frequently-updated list; medical reference texts such as the
                  physicians' desk reference may also provide this information; 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 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

               -  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 a
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Will be reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Response rates
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Will be using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1). Binomial proportions and their 95% confidence intervals will be used.
Measure:Effects of therapy on human immunodeficiency virus (HIV) viral load
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure:CD4+ cell counts
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure:CD8+ cell counts
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure:Pharmacokinetic parameters
Time Frame:Days 1, 22, and 23 of course 1
Safety Issue:
Description: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 nonparametric statistical testing techniques.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated