Clinical Trials /

Ponatinib in the Treatment of FGFR Mutation Positive Recurrent or Persistent Endometrial Carcinoma

NCT01888562

Description:

To test the patient's cancerous tumor to see if it has a FGFR mutation and, if so, to see how their cancer responds to a treatment with the drug ponatinib as well as examine the side effects caused by ponatinib.

Related Conditions:
  • Endometrioid Adenocarcinoma
Recruiting Status:

Withdrawn

Phase:

N/A

Trial Eligibility

Document

Title

  • Brief Title: Ponatinib in the Treatment of FGFR Mutation Positive Recurrent or Persistent Endometrial Carcinoma
  • Official Title: A Pilot Evaluation of Ponatinib (AP24534), a Potent Oral Pan-FGFR Inhibitor, in the Treatment of FGFR Mutation Positive Recurrent or Persistent Endometrial Carcinoma: a Multi-Institutional Study

Clinical Trial IDs

  • ORG STUDY ID: 201404024
  • NCT ID: NCT01888562

Conditions

  • Endometrial Neoplasms

Interventions

DrugSynonymsArms
PonatinibIclusigPonatinib

Purpose

To test the patient's cancerous tumor to see if it has a FGFR mutation and, if so, to see how their cancer responds to a treatment with the drug ponatinib as well as examine the side effects caused by ponatinib.

Trial Arms

NameTypeDescriptionInterventions
PonatinibExperimentalPonatinib 45mg po daily for 4 weeks (4 weeks equal 1 cycle).
  • Ponatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have recurrent or persistent endometrial carcinoma which is refractory
             to curative therapy or established treatments. Histologic confirmation of the original
             primary tumor is required. Patients with the following histologic epithelial cell
             types are eligible: endometrioid adenocarcinoma.

          -  All patients must have measurable disease. Measurable disease is defined as at least
             one lesion that can be accurately measured in at least one dimension (longest
             dimension to be recorded). Each lesion must be ≥ 20 mm when measured by conventional
             techniques, including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when measured by
             spiral CT.

        Patients must have at least one "target lesion" to be used to assess response on this
        protocol as defined by RECIST 1.1 (Section 11.1). 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 have a documented FGFR2 activating mutation either on primary, recurrent
             or metastatic biopsy. Over 90% of FGFR2 mutations occur at 7 codons. Activating
             mutations are defined as the known FGFR2 hotspots at S252W, P253R, S373C, Y376C,
             C383R, N550K, N550H, K660E.

          -  Patients who have received one or two prior regimen must have a GOG Performance Status
             of 0, 1, or 2. Patients who have received three prior regimens must have a GOG
             Performance Status of 0 or 1.

          -  Patients must be ≥ 18 years of age.

          -  Patients must be able to swallow tablets.

          -  Patients must have recovered from the effects of recent surgery, radiotherapy, or
             chemotherapy.

          -  Patients should be free of active infection requiring antibiotics (with the exception
             of uncomplicated UTI).

          -  Any hormonal therapy directed at the malignant tumor must be discontinued at least one
             week prior to registration.

          -  Any other prior therapy directed at the malignant tumor, including immunologic agents,
             must be discontinued at least three weeks prior to registration.

          -  Patients must have had at least one prior chemotherapeutic regimen for management of
             endometrial carcinoma. Chemotherapy administered in conjunction with primary radiation
             as a radio-sensitizer will be counted as a systemic chemotherapy regimen. Patients may
             have received prior anti-angiogenic compounds (i.e., bevacizumab).

        Patients are allowed to receive, but are not required to receive, up to two additional
        cytotoxic regimens for management of recurrent or persistent endometrial disease according
        to the following definition:

        Cytotoxic regimens include any agent that targets the genetic and/or mitotic apparatus of
        dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or
        gastrointestinal mucosa.

          -  Patients must have adequate bone marrow function defined as:

               -  Absolute neutrophil count (ANC) ≥ 1,500/mcl

               -  Platelets ≥ 100,000/mcl

               -  Hemoglobin > 9 g/dl

          -  Patients must have adequate renal function defined as:

             • Creatinine ≤ 1.5 x institutional upper limit normal (ULN)

          -  Proteinuria must be ≤ 3+ by dipstick at baseline. If the urine dipstick is > 3+, a
             24-hour protein level must be performed. The 24-hour protein level must be ≤ 3.5 g/24
             hours.

          -  Patients must have adequate hepatic function defined as:

               -  Bilirubin ≤ 1.5 x ULN

               -  AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 2.5 x ULN

               -  Albumin ≥ 2.5 g/dl

          -  Patients must have adequate neurologic function defined as:

             • Neuropathy (sensory and motor) ≤ grade 1

          -  Patients must have adequate blood coagulation parameters defined as:

               -  PT such that international normalized ratio (INR) is ≤ 1.5

        Patients on therapeutic warfarin are excluded from trial; anticoagulation with a heparin or
        heparin-like compound is permitted provided patient's PT INR is ≤ 1.5.

          -  Patients must be able to understand and willing to sign an approved informed consent
             and authorization permitting release of personal health information.

          -  Patients of childbearing potential must have a negative serum pregnancy test performed
             48 hours prior to first dose and be practicing an effective form of contraception
             during the study and for at least 3 months after receiving the final treatment of
             ponatinib. Effective contraception is defined as hormonal or barrier method, or
             abstinence.

          -  Patients must have a baseline electrocardiogram completed prior to study entry with
             QTc ≤ 450 msec. Baseline ECG should be repeated if QTc is found to be > 450 msec. QTc
             must NOT be > 450 msec on both ECGs performed during the same visit.

        Exclusion Criteria:

          -  Patients must not have had prior therapy with ponatinib or anti-FGFR (fibroblast
             growth factor receptor) therapy including brivanib, BIBF1120, and E7080.

          -  Patients with a history of other invasive malignancies, with the exception of
             non-melanoma skin cancer, localized cancer of the breast, and localized cancer of the
             head and neck, are excluded if there is any evidence of the other malignancy being
             present within the last five 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 OTHER THAN for the treatment of endometrial cancer within the last five
             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 endometrial cancer within the last five 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 that
             the patient remains free of recurrent or metastatic disease.

          -  Patients must not be on required chronic anti-platelet therapy (aspirin >300 mg/day,
             or clopidogrel greater than or equal to 75mg/day).

          -  Patients must not have any gastrointestinal bleeding or any other hemorrhage/bleeding
             event ≥ grade 3 within 30 days prior to study entry.

          -  Patients must not have a history of poor wound healing, non-healing ulcers or bone
             fractures within the last 3 months.

          -  Patients must not have uncontrolled or significant cardiovascular disease including:

               -  Myocardial infarction within 3 months

               -  Uncontrolled angina within 3 months

               -  Class III-IV New York Heart Association (NYHA) congestive heart failure (see
                  Appendix B)

               -  Uncontrolled hypertension (systolic BP > 150 or diastolic BP > 100 mmHg for 24
                  hours) despite optimized anti-hypertensive therapy. BP must be below 150/100 mmHg
                  at screening. Subjects with a history of hypertension who are receiving treatment
                  with calcium channel blockers that are CYP3A4 inhibitors should be changed to an
                  alternative antihypertensive medication before study entry

               -  History of stroke, TIA, or other CNS ischemic event

               -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
                  digoxin

               -  Pre-therapy Left Ventricle Ejection Fraction (LVEF) ≤ 50%

               -  Valvular heart disease ≥ grade 2

          -  Patients must not have a serious uncontrolled medical disorder or active infection
             which would impair the ability of the subject to receive protocol therapy or whose
             control may be jeopardized by the complications of this therapy.

          -  Patients must not have any pre-existing thyroid abnormality with thyroid function that
             cannot be maintained in the institutional normal range with medication.

          -  Patients must not have hyponatremia (sodium < 130mEq/L).

          -  Patients must not have active/known HIV, Hepatitis B, or Hepatitis C.

          -  Patients must not have known brain metastases. Patients with known brain metastases
             will be excluded from this clinical trial because of their poor prognosis and because
             they often develop progressive neurological dysfunction that would confound the
             evaluation of neurologic and other adverse events.

          -  Patients must not have a history of allergic reactions attributed to compounds of
             similar chemical or biological composition to ponatinib or other agents used in this
             study.

          -  Patients must not be pregnant or nursing.

          -  Patients must not have untreated malabsorption syndrome.

          -  Patients must not have baseline serum potassium < 3.5 mmol/L (potassium
             supplementation may be given to restore the serum potassium above this level prior to
             study entry).

          -  Patients on therapeutic warfarin anticoagulation will be excluded. Patients converted
             to anticoagulation with a heparin compound will be allowed provided the PT INR is ≤
             1.5.

          -  Patients with:

               1. History of acute pancreatitis within 1 year of study or history of chronic
                  pancreatitis

               2. History of alcohol abuse

               3. History of uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

          -  Women and Minorities

        Participating institutions will not exclude potential subjects from participating in this
        or any study solely on the basis of ethnic origin or socioeconomic status. Every attempt
        will be made to enter all eligible patients into this protocol and therefore address the
        study objectives in a patient population representative of the entire endometrial cancer
        population treated by participating institutions.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor responses (CR + PR)
Time Frame:6 months
Safety Issue:
Description:Ponatinib in patients with recurrent or persistent endometrioid endometrial cancer (FGFR2 activating mutation positive)for tumor responses (CR + PR) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:5.5 years
Safety Issue:
Description:Progression Free Survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:overall survival
Time Frame:5.5 years
Safety Issue:
Description:Overall survival is define as date from time of initial treatment to date of death from any cause.
Measure:Toxicity of Ponatinib
Time Frame:1 year
Safety Issue:
Description:Frequency and severity as defined by CTCAE v 4.0

Details

Phase:N/A
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Washington University School of Medicine

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