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Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by NPM Pharma Inc.
Sponsor:
Collaborator:
Karyopharm Therapeutics, Inc
Information provided by (Responsible Party):
NPM Pharma Inc.
ClinicalTrials.gov Identifier:
NCT01607892
First received: May 16, 2012
Last updated: April 11, 2014
Last verified: April 2014

May 16, 2012
April 11, 2014
June 2012
January 2016   (final data collection date for primary outcome measure)
Number of participants with Adverse Events [ Time Frame: 2 and 12 months ] [ Designated as safety issue: Yes ]
Severity of Adverse Events
Same as current
Complete list of historical versions of study NCT01607892 on ClinicalTrials.gov Archive Site
Area under the plasma concentration versus time curve (AUC) of KPT-330 [ Time Frame: 2 and 12 months ] [ Designated as safety issue: No ]
Changes in AUC over time
Same as current
Not Provided
Not Provided
 
Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Malignancies

The purpose of this research study are to find out more information such as: the highest dose of KPT-330 that can be given safely, the side effects it may cause, to examine how the body affects the study drug concentrations in the blood (pharmacokinetics or PK), to examine the effects of this study drug on the body (pharmacodynamics or PDn) and to gain some information on its effectiveness in treating cancer.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Hematological Malignancies
Drug: KPT-330

Schedule 1 & 2 no longer enrolling

Schedule 3: Starting dose ≥ 30mg/m2, 2X/week on D1 & D3 each week. Total of 8 dose/cycle.

Schedule 4: Starting dose will be ≥ 23mg/m2, 2x/wk on D1 & D2 of each week. Total of 8 doses/cycle.

Schedule 5: Starting dose will be ≥ 30mg/m2, 2x/week on D1 and D4 of each week. Total of 8 doses/cycle.

Schedule 6: Starting dose ≥ 35mg/m2, 2X/week on D1&D3 each week with 20mg Dex on each dosing day. Total of 8 dose/cycle.

Schedule 7: Starting dose will be ≥ 45mg/m2, once a week. Total of 4 doses/cycle.

Schedule 8: Starting dose will be ≥ 45mg/m2, 2x/week during the first 2 weeks on Days 1, 3, 8, and 10, followed by an 11-day treatment free interval in each 3 week cycle. Total of 4 doses/cycle.

  • Chronic Hematological Malignancies
    This Arm includes patients with "chronic" hematological malignancies.
    Intervention: Drug: KPT-330
  • Acute Myeloid Leukemia (AML)
    Patients with all types of relapsed/refractory or non-chemotherapy candidate AML, except acute promyelocytic leukemia (APL) will be included in this Arm.
    Intervention: Drug: KPT-330
  • Dose Expansion Cohort
    Peripheral (PTCL) and Cutaneous (CTCL) T Cell Lymphoma Up to 12 patients with relapsed / refractory PTCL or CTCL will be enrolled in this cohort at a dose of 30mg/m2 twice weekly (Schedule 3).
    Intervention: Drug: KPT-330
  • Acute Lymphoblastic Leukemia (B- or T- cell)
    This is an expansion cohort for relapsed/refractory ALL
    Intervention: Drug: KPT-330
  • Chronic Myelocytic Leukemia (CML)
    This is an Expansion cohort for Accelerated or blast crisis phase
    Intervention: Drug: KPT-330
  • Multiple Myeloma and Waldenstroms
    This is an expansion cohort for only MM and WM patients
    Intervention: Drug: KPT-330
Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, Tiedemann RE, Palmer SE, Garbitt VM, McCauley D, Kauffman M, Shacham S, Chesi M, Bergsagel PL, Stewart AK. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013 Dec;27(12):2357-65. doi: 10.1038/leu.2013.172. Epub 2013 Jun 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
249
Not Provided
January 2016   (final data collection date for primary outcome measure)

Inclusion Criteria

  1. Written informed consent in accordance with federal, local, and institutional guidelines
  2. Age ≥18 years
  3. Patients with malignancies that are refractory to or who are intolerant of established therapy known to provide clinical benefit for their condition. Patients must not be candidates for anti-tumor regimens known to provide clinical benefit
  4. Arm 1 Dose Escalation Phase: Histologically confirmed diagnosis, and evidence of disease progression, of Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), or Waldenstrom's Macroglobulinemia (WM) as described below:

    Multiple Myeloma (MM): Symptomatic disease previously treated with ≥3 prior regimens (lines of therapy) that included at least one of each of the following: an alkylating agent, an immunomodulatory drug, a proteasome inhibitor, and a steroid. Patients must have measurable disease as defined by at least one of the following:

    1. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA myeloma, by quantitative IgA; or
    2. Urinary M-protein excretion at least 200 mg/24 hours; or
    3. Serum Free Light Chain (SFLC) whereby the involved light chain measures ≥ 10 mg/dL and with an abnormal ratio

    Non-Hodgkin's Lymphoma (NHL): Advanced indolent or aggressive NHL according to the WHO classification, having been treated with ≥2 prior regimens including rituximab (for B cell NHL only), an alkylating agent, and steroids. Patients with cutaneous T cell lymphoma (CTCL) or Peripheral T Cell Leukemia (PTCL) are excluded from this study.

    Chronic Lymphocytic Leukemia (CLL): advanced, relapsed CLL after having received fludarabine (if medically appropriate), an alkylating agent, and rituximab as part of one or more of their previous regimens.

    Waldenström's Macroglobulinemia (WM): relapsed WM after at least 2 prior regimens (lines of therapy) that included at least one proteasome inhibitor and at least one steroid.

    Arm 1: Dose Expansion Phase:

    • Up to 10 patients with MM or WM: Symptomatic disease previously treated with, and relapsed or refractory to, ≥3 prior regimens (lines of therapy) that included at least one of each of the following: an alkylating agent, an immunomodulatory drug, a proteasome inhibitor, and a steroid. Patients must have measurable disease as defined by at least one of the following:

      1. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA myeloma, by quantitative IgA; or
      2. Urinary M-protein excretion at least 200 mg/24 hours; or
      3. Serum Free Light Chain (SFLC) whereby the involved light chain measures ≥ 10 mg/dL and with an abnormal ratio.
    • Up to 15 patients with relapsed or refractory Diffuse Large B Cell Lymphoma (DLBCL):

      1. Biopsy-proven aggressive Diffuse Large B-Cell Lymphoma of any genetic subtype.
      2. Relapsed or refractory to previous therapy for lymphoma.
      3. Must have received at least one prior combination chemotherapy regimen. There is no limit on the number of prior therapies.
      4. Patients must have an autologous stem cell transplant if they were eligible for it.
      5. Patients must have measurable disease on cross sectional imaging that is at least 2 cm in the longest diameter.

    Arm 2 Dose Escalation and Expansion Phases: Histologically confirmed diagnosis of AML according to the WHO classification (any subtype except for Acute Promyelocytic Leukemia (APL)) with disease progression after chemotherapy, or not a chemotherapy candidate as defined as:

    • Refractory disease as defined: Persistent disease after at least two induction cycles (e.g., 3+7 and 2+5), or at least one high dose arabinoside-C (Ara-C) containing regimen; or
    • Relapsed AML: unlikely to benefit from chemotherapy (second or subsequent relapse, any relapse patients failing salvage chemotherapy, or patients in first relapse with less than one year disease free interval; or
    • Non-chemotherapy candidates: Previously untreated older adults (> age 60) with at least one of the following risk factors: age >70 years, antecedent hematological disease, non-favorable chromosome analysis.

    Dose Expansion Cohort Approximately 25 eligible patients with MM or WM (N=10) and DLBCL (N=15) will be enrolled into the dose expansion cohort in Arm 1 as described above

    Approximately 24 eligible patients AML as described in the escalation cohort above will be enrolled into the dose expansion cohort in Arm 2.

    Arm 3 Dose Expansion Phase: Histologically confirmed diagnosis of CTCL or PTCL (any subtype) following treatment with at least two prior therapies.

    • PTCL: patients must have relapsed or refractory to at least one prior chemotherapy regimen, and have relapsed from, or are intolerant to, both romidepsin and pralatrexate.
    • CTCL: patients must extensive disease and have relapsed after at least one prior chemotherapy regimen as well as from romidepsin.
  5. All patients on this study must have evidence of progressive disease on study entry. Previously untreated patients who are not chemotherapy candidates on Arm 2 may have advanced disease (without clear progression). There is no upper limit on the number of prior treatments provided all inclusion/exclusion criteria are met.
  6. Dose Escalation Phase: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 1 (Appendix 1). Dose Expansion Phase: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 1 (Appendix 1).
  7. Adequate hepatic function within 14 days prior to C1D1: total bilirubin <2 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 times ULN), asparate aminotransferase (AST) <2.5 times ULN and alanine aminotransferase (ALT) <2.5 times ULN. In the case of known (radiological and/or biopsy documented) liver metastasis, AST <5.0 times ULN and ALT <5.0 times ULN is acceptable;
  8. Adequate renal function within 14 days prior to C1D1: estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockcroft and Gault: (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female.
  9. Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
  10. Arm 1 & 3 only: Patients receiving hematopoietic growth factor support including erythropoietin, darbepoetin, G-CSF, GM-CSF, and platelet stimulators can continue to do so, but must be transfusion independent for at least 3 weeks prior to registration in the dose escalation phase of the study. Elective transfusions are permitted for transfusion independent patients during the 3-week period prior to dosing. There are no restrictions on transfusions for enrollment into and during the dose expansion phase of the study. Screening absolute neutrophil count (ANC) should be independent of growth factor support for at least 1 week prior to registration for all patients.
  11. Arm 1 & 3 only: Adequate hematopoietic function (excluding patients with acute leukemia) within 14 days prior to C1D1: total white blood cell (WBC) count ≥1,500/mm3, absolute neutrophil count (ANC) ≥800/mm3, hemoglobin (Hb) ≥8.0gm/dL, and platelet count ≥30,000/mm3. Screening ANC should be independent of growth factor support for >1 week for all patients.

Exclusion Criteria

  1. Patients who are pregnant or lactating;
  2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks prior to cycle 1 day 1 and mitomycin C and radioimmunotherapy 6 weeks prior to cycle 1 day 1. For CLL and NHL palliative steroids for disease related symptoms are allowed up to 3 days prior to starting therapy. For patients in Arm 2, Hydroxyurea may be given prior to, and during the first cycle of treatment with KPT-330;
  3. Patients with active graft versus host disease after allogeneic stem cell transplantation. At least 3 months must have elapsed since completion of allogeneic stem cell transplantation except for patients with AML, where at least 2 months must have elapsed;
  4. Major surgery within four weeks before Day 1;
  5. Unstable cardiovascular function:

    • symptomatic ischemia, or
    • uncontrolled clinically significant conduction abnormalities (ie: ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
    • congestive heart failure (CHF) of NYHA Class ≥3, or
    • myocardial infarction (MI) within 3 months;
  6. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose;
  7. Known to be HIV seropositive;
  8. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen);
  9. Patients with active CNS malignancy. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months. Patient with malignant cells in their cerebrospinal fluid (CSF) without CNS symptom may be included.
  10. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea.
  11. Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
  12. History of seizures, movement disorders or cerebrovascular accident within the past 5 years prior to cycle 1 day 1.
  13. Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity.
  14. In the opinion of the investigator, patients who are significantly below their ideal body weight.
  15. Serious psychiatric or medical conditions that could interfere with treatment.
  16. Participation in an investigational anti-cancer study within 3 weeks prior to first dose of study drug;
  17. Concurrent therapy with approved or investigational anticancer therapeutic other than steroids or hydroxyurea as specified above.
Both
18 Years and older
No
Contact: Michael Kauffman, MD, PhD 508-975-4822 mkauffman@karyopharm.com
United States,   Canada,   Denmark
 
NCT01607892
KCP-330-001
Not Provided
NPM Pharma Inc.
NPM Pharma Inc.
Karyopharm Therapeutics, Inc
Not Provided
NPM Pharma Inc.
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP