Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Dana-Farber Cancer Institute
Sponsor:
Collaborators:
William Lawrence and Blanche Hughes Foundation
Karyopharm Therapeutics, Inc
Information provided by (Responsible Party):
Andrew E. Place, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT02091245
First received: March 14, 2014
Last updated: August 3, 2016
Last verified: August 2016
  Purpose
This research study involves participants who have acute lymphoblastic or acute myelogenous leukemia that has relapsed or has become resistant (or refractory) to standard therapies. This research study is evaluating a drug called KPT-330. Laboratory and other studies suggest that the study drug, KPT-330, may prevent leukemia cells from growing and may lead to the destruction of leukemia cells. It is thought that KPT-330 activates cellular processes that increase the death of leukemia cells. The main goal of this study is to evaluate the side effects of KPT-330 when it is administered to children and adolescents with relapsed or refractory leukemia.

Condition Intervention Phase
Relapsed Acute Lymphoblastic Leukemia (ALL)
Refractory Acute Lymphoblastic Leukemia (ALL)
Relapsed Acute Myelogenous Leukemia (AML)
Refractory Acute Myelogenous Leukemia (AML)
Relapsed Mixed Lineage Leukemia
Refractory Mixed Lineage Leukemia
Relapsed Biphenotypic Leukemia
Refractory Biphenotypic Leukemia
Chronic Myelogenous Leukemia (CML) in Blast Crisis
Drug: KPT-330
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML.

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Toxicity profile of KPT-330 assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 3 Years ] [ Designated as safety issue: Yes ]
    Toxicities will be tabulated by type and grade.

  • Maximum tolerated dose (MTD) of KPT-330 determined by incidence of dose limiting toxicities. [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]
    Toxicities graded by CTCAE version 4.0


Secondary Outcome Measures:
  • Measurement of KPT-330 in the blood, urine and cerebrospinal fluid. [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    Pharmacokinetic analysis

  • Assessment of anti-leukemic activity of KPT-330 measured by objective response rates. [ Time Frame: 3 Years ] [ Designated as safety issue: No ]
  • Biomarker analysis including measurements of cytokine levels and expression of XPO1 in white blood cells. [ Time Frame: 3 Years ] [ Designated as safety issue: No ]
    Pharmacodynamic analysis


Estimated Enrollment: 28
Study Start Date: March 2014
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: KPT-330
KPT-330 will be administered twice a week on Days 1 and 3 for four weeks. Starting dose 30 mg/m2.In the dose-escalation cohort, three patients will initially be enrolled at each dose level and will be monitored for a DLT during the 28-day treatment cycle before dose escalation may occur.
Drug: KPT-330
Other Name: Selinexor

Detailed Description:

The investigators are trying to determine a safe dose of KPT-330 and will be giving participants different dose levels of the study drug. Three to six participants will receive the starting dose of the drug. If the side effects are not too severe, the next group of participants will take the study drug at a higher dose level. Up to 3 dose levels of the study drug will be tested, but once each participant has been assigned a dose level, the participant will always receive the same dose. The highest dose that people can be given safely is called the maximum tolerated dose (MTD). Once the MTD is determined, up to 10 additional participants will receive that dose to further study the drug.

Participants between the age of ≥18 months (540 days) and ≤ 21 years with relapsed (second or subsequent relapse) or refractory ALL or AML will be eligible to enroll. KPT-330 will be administered twice a week on Days 1 and 3 for four weeks (a cycle is 4 weeks). All participants will receive intrathecal chemotherapy on Day 1 of each cycle. Participants with CNS-2 disease will receive additional doses of IT chemo. Pharmacokinetic (PK) samples will be collected during Cycle 1 on Days 1-3 and 15. PK samples will be collected during Cycle 2 on Day 15. Pharmacodynamic (PD) samples will be collected during Cycle 1 on Days 1-3. PD samples will be collected during Cycle 2 on Day 15. Additional optional correlative biology sample will be collected. Participants are monitored closely for adverse events. Participants will have physical exams and blood work more than once a week during all cycles.

  Eligibility

Ages Eligible for Study:   18 Months to 21 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age: Patient must be ≥ 18 months (540 days) and ≤ 21 years.
  • Histologically confirmed diagnosis of relapsed or refractory ALL (including Burkitt leukemia), AML, mixed lineage leukemia, biphenotypic leukemia, or chronic myelogenous leukemia (CML) in blast crisis.

    • Refractory disease defined as: Persistent disease after at least two induction cycles.
    • Relapsed disease: Second or subsequent relapse, any relapse refractory to salvage chemotherapy
  • Patients must have bone marrow with ≥ 5% blasts (M2 or M3 marrow) either on an aspirate or biopsy sample, as assessed by morphology or flow cytometry.
  • Patients with CNS 1 or CNS 2 disease are eligible. Patients with isolated CNS relapse or CNS 3 disease are not eligible. Please refer to Section 11.1.3 for definitions of CNS disease status and interpretation of traumatic lumbar punctures.
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all of the following criteria:

    • Myelosuppressive chemotherapy: 14 days must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications within 14 days without a "wash-out" period:

      • Standard maintenance therapy (vincristine, 6MP, corticosteroids, low dose methotrexate)
      • Hydroxyurea
      • Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine.
    • Radiation therapy (XRT):

      • Total Body Irradiation (TBI) or craniospinal radiation therapy: Must have been completed more than 90 days from study entry
      • Palliative XRT: XRT for chloromas does not require a washout period.
    • Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    • Immunotherapy: At least 6 weeks after the completion of any type of immunotherapy, e.g. tumor vaccines.
    • Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody. (See table on DVL homepage listing monoclonal antibody half-lives: https://members.childrensoncologygroup.
  • Performance status:

    -- Lansky ≥ 50 for individuals 18 months- ≤ 16 years old; Karnofsky > 50% for individuals 17-21 years old (See Appendix I).

  • Adequate organ function defined as the following:

    • Direct bilirubin ≤1.5 X institutional upper limit of normal (ULN)
    • AST (SGOT)/ALT (SGPT) ≤ 3X institutional ULN
    • Creatinine below institutional ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal
    • Echocardiogram must have a shortening fraction or an ejection fraction greater than institutional lower limit of normal for age and gender.
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
  • Female patients with infants must agree not to breastfeed their infants while on this study.
  • The effects of KPT-330 on the developing human fetus are unknown. For this reason and because many chemotherapeutic agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability of participant (or parent/guardian for participants who are minors) to understand and the willingness to sign the written informed consent document.

Exclusion Criteria:Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

  • Inability to take or tolerate enteral medications
  • Individuals with CNS 3 leukemia
  • Individuals with Down syndrome
  • Patients with prior hematopoietic stem cell transplant (HSCT) are eligible, with the exception of the following:

    • Autologous HSCT within 60 days of study entry
    • Allogeneic HSCT within 90 days of study entry
    • Evidence of graft-versus-host-disease (GVHD)
    • Treatment with immunosuppressive medications within 14 days; however, weaning or stable doses of steroids (must be ≤ 20 mg/m2/day of prednisone equivalents) and/or calcineurin inhibitors are permitted.
  • Treatment with hematopoietic growth factors (G-CSF):

    • Long-acting (e.g., Neulasta) within 14 days prior to study entry
    • Short-acting (e.g., Neupogen) within 7 days prior to study entry
  • Treatment with an investigational agent within 28 days of study entry, or 3 half-lives, whichever is longer.
  • Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
  • Any ECG abnormality that in the opinion of the principal investigator would preclude safe participation in the study
  • Patients refractory to red blood cell or platelet transfusions.
  • Patients receiving anti-coagulation therapy are eligible as long as anti-coagulation regimen has been stable for > 1 month.
  • Patients with systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  • For dose-escalation cohort only, known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required. HIV positive patients will be eligible for the dose-expansion cohort.
  • Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); baseline testing for viral hepatitis is not required.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of KPT-330 (e.g. ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption or history of small bowel resection)
  • Individuals with significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  • Individuals with a history of a different malignancy (other than acute leukemia) are ineligible except for the following circumstances: Individuals are eligible if the different malignancy is in complete remission at the time of study entry.
  • Pregnant women are excluded from this study because KPT-330 is a chemotherapeutic agent with unknown teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with study agents, breastfeeding is not allowed during study treatment.
  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: NCT02091245

Contacts
Contact: Andrew E Place, MD, PhD (617) 632-2313 aplace@partners.org

Locations
United States, California
UCSF Recruiting
San Francisco, California, United States, 94143
Contact: Elliot Stieglitz, MD       elliot.stieglitz@ucsf.edu   
Principal Investigator: Elliot Stieglitz, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Lia Gore, MD    720-777-6772    lia.gore@ucdenver.edu   
Principal Investigator: Lia Gore, MD         
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Melinda Pauly, MD       melinda.pauly@choa.org   
Principal Investigator: Melinda Pauly, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Andrew E Place, MD, PhD    617-632-2313    aplace@partners.org   
Principal Investigator: Andrew E Place, MD, PhD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Andrew E Place, MD    617-632-2313    aplace@partners.org   
Principal Investigator: Andrew E Place, MD, PhD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Maria-Luisa Sulis, MD       mls95@cumc.columbia.edu   
Principal Investigator: Maria L Sulis, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Richard Aplenc, MD       raplenc@mail.med.upenn.edu   
Principal Investigator: Richard Aplenc, MD         
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Rachel Rau, MD       rerau@bcm.edu   
Principal Investigator: Rachel Rau, MD         
United States, Washington
Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98101
Contact: Todd Cooper, DO       todd.cooper@seattlechidlrens.org   
Principal Investigator: Todd Cooper, DO         
United States, Wisconsin
Children's Hospital of Wisconsin Not yet recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Michael Burke, MD    414-955-4198    mmburke@mcw.edu   
Principal Investigator: Michael Burke, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
William Lawrence and Blanche Hughes Foundation
Karyopharm Therapeutics, Inc
Investigators
Principal Investigator: Andrew E Place, MD,PhD Dana-Farber Cancer Institute
  More Information

Responsible Party: Andrew E. Place, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02091245     History of Changes
Other Study ID Numbers: 13-563 
Study First Received: March 14, 2014
Last Updated: August 3, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
Relapsed acute lymphoblastic leukemia (ALL)
Refractory acute lymphoblastic leukemia (ALL)
Relapsed acute myelogenous leukemia (AML)
Refractory acute myelogenous leukemia (AML)
Relapsed childhood leukemia
Relapsed mixed lineage leukemia
Refractory mixed lineage leukemia
Relapsed biphenotypic leukemia
Refractory biphenotypic leukemia
Chronic myelogenous leukemia (CML) in blast crisis

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute
Blast Crisis
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes

ClinicalTrials.gov processed this record on December 02, 2016