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Phase I Trial of Cabozantinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01961765
Recruitment Status : Completed
First Posted : October 11, 2013
Last Update Posted : July 21, 2017
Information provided by (Responsible Party):
Amir Fathi, Massachusetts General Hospital

Brief Summary:

This research study is evaluating a drug called cabozantinib as a possible treatment for acute myeloid leukemia (AML). This research study is a Phase I clinical trial. Phase I trials test the safety of an investigational drug or combination of drugs. Phase I studies also try to define the appropriate dose of the investigational drug to use for further studies. This means that the FDA has not approved giving cabozantinib for use in patients, including patients with your type of cancer.

The study drug cabozantinib works by inhibiting several different proteins which are believed to be involved in the growth and multiplication of the cancerous cells associated with acute myeloid leukemia. This drug has been used in other research studies and information from those other research studies suggests that this drug may help to prevent cancer growth.

The primary purpose of this research study is to determine the highest dose of Cabozantinib that can safely be given without severe or unmanageable side effects. The dose identified in this study will be used in future research studies that seek to determine the role of cabozantinib as a treatment for AML.

Condition or disease Intervention/treatment Phase
Relapsed Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: cabozantinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Cabozantinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML).
Actual Study Start Date : November 2013
Actual Primary Completion Date : May 2016
Actual Study Completion Date : January 2017

Arm Intervention/treatment
Experimental: cabozantinib
Cabozantinib will be administered at a dose of 40mg daily by mouth in the first cohort. Dose escalation will occur in subsequent patient cohorts. We will evaluate 3-6 patients per dose level.
Drug: cabozantinib

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of cabozantinib in patients with advanced acute myeloid leukemia [ Time Frame: 2 Years ]
    To define the maximum tolerated dose (MTD) of cabozantinib in patients with advanced acute myeloid leukemia

Secondary Outcome Measures :
  1. Number of patients with adverse events including grade 3/4 adverse events [ Time Frame: 2 Years ]
    To evaluate the safety and tolerability of cabozantinib in adults with acute myeloid leukemia by assessing the number of patients who develop adverse events and assessing severity of these events

  2. Response rate [ Time Frame: 2 Years ]
    To determine the response rate in patients on study

  3. Progression-free survival after treatment [ Time Frame: 2 Years ]
    To measure the progression-free survival after treatment

  4. Pharmacodynamic effects of MET and FLT3 inhibition [ Time Frame: 2 Years ]
    To assess pharmacodynamic effects of MET and FLT3 inhibition, including plasma inhibitory assays for FLT3 phosphorylation, as well as MET expression levels during treatment

  5. Rate of disease remission [ Time Frame: 2 years ]
    To assess the rate of disease remission in terms of complete or partial remission in patients receiving therapy

  6. Overall survival after treatment [ Time Frame: 2 Years ]
    To measure the overall survival of patients after treatment

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Adults, 18 years of age and older, with pathologically confirmed, relapsed or refractory acute myelogenous leukemia OR those 70 and older who are not candidates for, or decline, conventional front line chemotherapy.
  • White blood cell count (WBC) should be lower than 30,000/mm3 prior to initiation of cabozantinib (Patients who are otherwise medically eligible for enrollment but have a WBC above 30,000/mm3 are allowed concurrent treatment with hydroxyurea and/or 6-mercaptopurine to stabilize the WBC for up to 15 days of therapy. In these situations, hydroxyurea and/or 6-mercaptopurine will be discontinued once WBC is below 10,000/mm3)
  • The subject has laboratory values as follows within 7 days prior to enrollment:
  • Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL
  • Serum albumin ≥ 2.8 g/dl
  • Serum creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:
  • Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72)
  • Female: Multiply above result by 0.85
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN
  • Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
  • Urine protein/creatinine ratio (UPCR) ≤ 1
  • Serum phosphorus >2.5, calcium > 8.4, magnesium >1.3, and potassium >3.3. Electrolyte repletion is allowed to reach these values.
  • ECOG performance status 0-1.
  • LVEF must be equal to or greater than 50%, as measured by MUGA scan or echocardiogram
  • Patients, or appropriate designee, must be able to provide informed consent.
  • 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 4 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 4 months after the last dose of study drug(s).
  • 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. Post-menopause 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, anti-estrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

  • Diagnosis of acute promyelocytic leukemia
  • Individuals with a history of other malignancies are ineligible unless:
  • They have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy
  • Have the following cancers if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
  • Subject has uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Subject has had prior treatment with cabozantinib
  • The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment
  • The subject has received systemic antineoplastic therapy within 14 days of study treatment, [However, hydroxyurea or 6-mercaptopurine can be given for the purposes of cytoreduction up to one day prior to enrollment, with the exceptions noted above in the inclusion criteria].
  • The subject has received radiation therapy:
  • to the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has with ongoing complications or is without complete recovery and healing from prior radiation therapy
  • to bone or brain metastasis within 14 days of the first dose of study treatment
  • The subject has received any investigational agent within 28 days before the first dose of study treatment.
  • The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
  • The subject has concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment.
  • Subjects who are HIV-positive on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with study drug. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Subject carries a diagnosis of active hepatitis B or C.
  • Subject has a current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF <50%, as measured by MUGA scan or echocardiogram)
  • The subject has a corrected QT interval (QTc) >500 ms at screening or has a history of long QT syndrome.
  • Subject has had clinically-significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
  • Subject has cavitating pulmonary lesion(s) or a pulmonary lesion or tumor abutting or encasing a major blood vessel.
  • Subject has received small-molecular kinase inhibitors or any other type of investigational agent within 4 weeks before the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is shorter.
  • The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results at screening ≥1.5 x the laboratory upper limit of normal.
  • The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or coumadin-related agents, thrombin or FXa inhibitors, and 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. Therapeutic anticoagulation with LMWHs may be allowed in certain circumstances as outlined as outlined in section 6.2.6.
  • The subject has uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening).
  • The subject has the following cardiac conditions: Unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including TIA, or other ischemic event) within 6 months of study treatment, myocardial infarction within 6 months of study treatment, history of thromboembolic event requiring therapeutic anticoagulation within 6 months of study treatment or main portal vein or vena cava thrombosis or occlusion. (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 at the time of screening
  • 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
  • Any of the following within 6 months before the first dose of study treatment:
  • history of 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 that 6 months ago.
  • Malabsorption syndrome
  • PEG tube placement within 3 months before the first dose of study therapy
  • Subject has 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
  • Subject is unable to swallow capsules or tablets.
  • The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort).
  • Subject is pregnant or breastfeeding.
  • Subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation.
  • Subject has systemic infection requiring IV antibiotic therapy within 7 days preceding the first dose of study drug, or other severe infection.
  • The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01961765

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United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Massachusetts General Hospital
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Principal Investigator: Amir Fathi, MD Massachusetts General Hospital

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Responsible Party: Amir Fathi, Principal Investigator, Massachusetts General Hospital Identifier: NCT01961765    
Other Study ID Numbers: 13-363
First Posted: October 11, 2013    Key Record Dates
Last Update Posted: July 21, 2017
Last Verified: July 2017
Keywords provided by Amir Fathi, Massachusetts General Hospital:
Relapsed acute myeloid leukemia
Refractory acute myeloid leukemia
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type