Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML
Phase: Phase 1
DFCI Protocol ID: 13-563
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.
Dana-Farber Cancer Institute, Children's Hospital Boston
Andrew Place, MD, PhD,
Dana Farber Cancer Institute
Dana-Farber Cancer Institute:
Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, email@example.com
- Age: Patient must be ̢�ۡ�� 18 months (540 days) and ̢�ۡ�_ 21 years.
- Histologically confirmed diagnosis of relapsed or refractory ALL, AML (any subtype
except for acute promyelocytic leukemia), mixed lineage leukemia or biphenotypic
leukemia with evidence of disease progression after prior therapy.
- Refractory disease defined as: Persistent disease after at least two induction
- Relapsed disease: Second or subsequent relapse, any relapse refractory to
- 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
- Intrathecal chemotherapy with methotrexate, hydrocortisone and/or
- 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
- 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 within normal institutional limits 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
- 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
- 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 a known t(9;22)/BCR-ABL fusion based on testing at either initial
diagnosis or at relapse.
- Individuals with mature B-cell leukemia defined by lymphoblasts expressing surface
immunoglobulin by flow cytometry and/or known t(8;14), t(2;8), or t(8;22).
- Absence of surface immunoglobulin by flow cytometry at time of relapse is sufficient
to rule out mature B-cell leukemia; karyotype or FISH results documenting absence of
t(8;14), t(2;8), or t(8;22) is not necessary prior to enrollment if absence of
surface of immunoglobulin is documented by flow cytometry.
- 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
- 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 ALL/AML) are
ineligible except for the following circumstances:
- Individuals are eligible if 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.
- Individuals with the following cancers are eligible if diagnosed and treated within
the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma
of the skin.
- 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.