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Safety Study of CAT-8015 to Treat Advanced B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (NHL or CLL)

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ClinicalTrials.gov Identifier: NCT01030536
Recruitment Status : Completed
First Posted : December 11, 2009
Results First Posted : April 9, 2018
Last Update Posted : April 9, 2018
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Brief Summary:
The primary objectives of this study are to determine the maximum tolerated dose (MTD) or optimal biologic dose (OBD) and safety profile of CAT-8015 in participants with relapsed or refractory advanced B-cell NHL (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL]) or CLL.

Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Chronic Lymphocytic Leukemia Drug: CAT-8015 20 mcg/kg Drug: CAT-8015 30 mcg/kg Drug: CAT-8015 40 mcg/kg Drug: CAT-8015 50 mcg/kg Drug: CAT-8015 60 mcg/kg Phase 1 Phase 2

Detailed Description:
To determine the maximum tolerated dose (MTD) or optimal biologic dose (OBD) of CAT-8015 in participants with relapsed or refractory advanced B-cell NHL (DLBCL, FL, MCL) or CLL.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of CAT-8015 in Adult Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
Actual Study Start Date : February 15, 2010
Actual Primary Completion Date : March 4, 2013
Actual Study Completion Date : March 4, 2013


Arm Intervention/treatment
Experimental: CAT-8015 20 microgram per kilogram (mcg/kg)
Participants will receive 20 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle. Dose escalation is to be continued to the Maximum tolerated dose (MTD) or Optimal biologic dose (OBD). Subsequent dose levels with a 10 mcg/kg increase from the previous dose level are possible if an MTD or OBD is not reached by 60 mcg/kg.
Drug: CAT-8015 20 mcg/kg
Participants will receive 20 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle.
Experimental: CAT-8015 30 mcg/kg
Participants will receive 30 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle. Dose escalation is to be continued to the Maximum tolerated dose (MTD) or Optimal biologic dose (OBD). Subsequent dose levels with a 10 mcg/kg increase from the previous dose level are possible if an MTD or OBD is not reached by 60 mcg/kg.
Drug: CAT-8015 30 mcg/kg
Participants will receive 30 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle.
Experimental: CAT-8015 40 mcg/kg
Participants will receive 40 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle. Dose escalation is to be continued to the Maximum tolerated dose (MTD) or Optimal biologic dose (OBD). Subsequent dose levels with a 10 mcg/kg increase from the previous dose level are possible if an MTD or OBD is not reached by 60 mcg/kg.
Drug: CAT-8015 40 mcg/kg
Participants will receive 40 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle.
Experimental: CAT-8015 50 mcg/kg
Participants will receive 50 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle. Dose escalation is to be continued to the Maximum tolerated dose (MTD) or Optimal biologic dose (OBD). Subsequent dose levels with a 10 mcg/kg increase from the previous dose level are possible if an MTD or OBD is not reached by 60 mcg/kg.
Drug: CAT-8015 50 mcg/kg
Participants will receive 50 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle.
Experimental: CAT-8015 60 mcg/kg
Participants will receive 60 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle. Dose escalation is to be continued to the Maximum tolerated dose (MTD) or Optimal biologic dose (OBD). Subsequent dose levels with a 10 mcg/kg increase from the previous dose level are possible if an MTD or OBD is not reached by 60 mcg/kg.
Drug: CAT-8015 60 mcg/kg
Participants will receive 60 mcg/kg Moxetumomab pasudotox (CAT-8015) as an intravenous (IV) infusion over 30 minutes on Days 1, 3, and 5 of every 28-day cycle.



Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Day 1 to end of Cycle 1 (approximately 28 days) ]
    MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity [DLT]) in more than 30 percent (%) of participants.

  2. Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Day 1 to end of Cycle 1 (approximately 28 days) ]
    Any Grade 3 or greater, non-hematological toxicity (including capillary leak syndrome [CLS] and thrombotic microangiopathy/ hemolytic uremic syndrome (HUS), Grade 3 or higher treatment-related hematologic toxicities and only ≥ Grade 3 thrombotic microangiopathy /HUS constituted a DLT with few exceptions.

  3. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: From Screening (Day -28) to Post Therapy Day 30 ]
    Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An Serious Adverse Event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.

  4. Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From Screening (Day -28) to Post Therapy Day 30 ]
    Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.

  5. Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From Screening (Day -28) to Post Therapy Day 30 ]
    Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.

  6. Number of Participants With Electrocardiogram (ECG) Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From Screening (Day -28) to Post Therapy Day 30 ]
    Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.


Secondary Outcome Measures :
  1. Percentage of Participants With Complete Response (CR) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    The CR rate was defined as the percentage of participants who had achieved CR based on both the evaluable population for efficacy.

  2. Duration of Complete Response [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    Duration of CR was measured from the first documentation of a CR to the time of relapse for the subgroup of participants with CR. Duration of CR was calculated using the Kaplan Meier method. The Evaluable Population for efficacy was used to evaluate the endpoints for the efficacy profile.

  3. Percentage of Participants With Partial Response (PR) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
  4. Percentage of Participants With Objective Response (OR) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    OR was defined as the percentage of participants with CR or partial response (PR).

  5. Time to Response (TTR) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    TTR was measured from the start of moxetumomab pasudotox administration to the first documentation of response (CR or PR) and was only assessed in participants who had achieved objective response (OR).

  6. Duration of Objective Response (DOR) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    DOR was measured from the first documentation of OR to the event of relapse. DOR was calculated using the Kaplan-Meier method.

  7. Duration of Stable Disease (SD) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]
    Duration of SD was defined as the time period from start of moxetumomab pasudotox administration to the event of progressive disease (PD)/relapse. Duration of SD was only calculated for the subgroup of participants with best response of CR, PR, or SD, and was calculated using the Kaplan-Meier method.

  8. Maximum Plasma Concentration (Cmax) of Moxetumomab Pasudotox [ Time Frame: Pre-dose and End of infusion on Day 1, 3 and 5 of each cycle; 1, 3 and 6 hour after the end of infusion on Day 1 of each cycle ]
    Maximum observed drug concentration of Moxetumomab pasudotox in plasma.

  9. Area Under Concentration-Time Curve From Dosing Extrapolated to Infinity (AUCinf) of Moxetumomab Pasudotox [ Time Frame: Pre-dose and End of infusion on Day 1, 3 and 5 of each cycle; 1, 3 and 6 hour after the end of infusion on Day 1 of each cycle ]
    Area under the concentration versus time curve from zero to infinity (AUC) of Moxetumomab pasudotox in Plasma.

  10. Clearance (CL) of Moxetumomab Pasudotox [ Time Frame: Pre-dose and End of infusion on Day 1, 3 and 5 of each cycle; 1, 3 and 6 hour after the end of infusion on Day 1 of each cycle ]
    CL of drug is rate at which drug is metabolized or eliminated by normal biological processes and is influenced by fraction of dose absorbed.

  11. Elimination Half Life (t1/2) of Moxetumomab Pasudotox [ Time Frame: Pre-dose and End of infusion on Day 1, 3 and 5 of each cycle; 1, 3 and 6 hour after the end of infusion on Day 1 of each cycle ]
    Plasma decay half life is the time measured for the plasma concentration to decrease by one half.

  12. Number of Participants With Positive Anti-Drug Antibody [ Time Frame: Baseline (Day 1) up to End of the Treatment (Last dose of Last cycle) (approximately 3 years) ]
    The moxetumomab pasudotox specific bridging assay using the Meso Scale Discovery platform was employed to detect anti-drug antibodies (ADA).

  13. Number of Participants With CD22 Expression Levels [ Time Frame: Baseline (Day 1) up to End of the Treatment (Last dose of Last cycle) (approximately 3 years) ]
    CD22 Expression was analyzed using Prism® analysis. Flow cytometry was performed to quantitate the CD22 expression for the purpose of evaluating the relationship of CD22 expression with response to treatment.

  14. Number of Capillary Leak Syndrome (CLS) Participants With Weight Changes, Albumin, Hypotension, Edema, Hypoxia, and Pulmonary Adverse Events (AEs) [ Time Frame: From Screening (Day -28) to Post Therapy Day 30 ]
    The correlation of CLS and weight changes, albumin, hypotension, edema, hypoxia, and pulmonary AEs were examined.

  15. Percentage of Participants With Stable Disease (SD) [ Time Frame: Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization
  • Participants must have histologically confirmed B-cell CLL, including small lymphocytic lymphoma (SLL), DLBCL, MCL, or FL
  • B-cell NHL: a) Have previous confirmation of B-cell NHL b) Participants with DLBCL or MCL, must have relapsed or refractory disease after at least one prior regimen containing rituximab, either alone or in combination, and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving c) Participants with FL, must have relapsed or refractory disease after at least two prior regimens, one of which included rituximab, either alone or in combination, and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving d) Have measurable disease (at least one lesion greater than or equal to (≥) 20 millimeter (mm) in one dimension or ≥ 15 mm in two dimensions as measured by conventional or high resolution [spiral] computed tomography e) Not be a candidate for a hematopoietic stem cell (HSC) or bone marrow transplant
  • B-cell CLL: a) Have previous confirmation of B-cell CLL with a characteristic immunophenotype by flow cytometry b) Have relapsed or refractory disease after at least 2 prior lines of treatment, at least 1 of which must have contained rituximab and be ineligible for any available standard line of therapy known to be life-prolonging or life-saving c) Not be a candidate for an HSC or BM transplant d) Have symptomatic disease that requires treatment
  • Karnofsky Performance Status ≥ 70
  • Life expectancy of ≥ 12 weeks
  • Toxicities from previous cancer therapies must have recovered to Grade less than (<) 2
  • Adequate hematological function defined as: a) Hemoglobin ≥ 9 g/dL b) Absolute neutrophil count ≥ 1500/mm^3 c) Platelet count ≥ 75,000/mm^3
  • Prothrombin time-International Normalized Ratio/Partial thromboplastin time less than or equal to (≤) 1.5 × upper limit of normal (ULN), or for participants on anticoagulation therapy, status within therapeutic range
  • Women of non-child-bearing potential or using effective contraception
  • Male participants with partners of child-bearing potential must be surgically sterile or use a contraceptive method

Exclusion Criteria:

  • Any available standard line of therapy known to be life-prolonging or life-saving
  • Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for treatment of cancer
  • For CLL participants only, rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy
  • History of allergy or reaction to any component of the CAT-8015
  • Receipt of any chemotherapy or small molecule targeted therapy or any biological- or immunological-based therapies for leukemia or lymphoma within 6 weeks
  • Prior radiation therapy will not be excluded, providing the volume of bone marrow treated is less than 25 percent
  • Any history of prior pseudomonas-exotoxin immunotoxin administration including CAT-8015, CAT-3888, or LMB-2
  • History of other invasive malignancy within 5 years, with some exceptions
  • Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic or antiviral therapy or for which other supportive care is given
  • Autologous stem cell transplantation within 6 months prior to study entry
  • Allogenic stem cell transplantation or any other organ transplant
  • HIV-positive or AIDS, Hepatitis B or hepatitis C infection as defined by seropositive for hepatitis B (HBsAg) or hepatitis C and elevated liver transaminases
  • Use of immunosuppressive medication other than steroids within 7 days, use of systemic steroids within 7 days before the first dose of CAT-8015 (inhaled and topical corticosteroids are permitted). Participants may take replacement doses of steroids (defined as ≤ 30 mg/day hydrocortisone or the equivalent) if on a stable dose for at least 2 weeks prior to the first dose of CAT-8015
  • Documented current central nervous system involvement by leukemia or lymphoma
  • Pregnancy or lactation, other severe, concurrent diseases
  • Concurrent enrollment in another clinical study

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 ClinicalTrials.gov identifier (NCT number): NCT01030536


Locations
United States, California
Research Site
Los Angeles, California, United States
United States, Indiana
Research Site
Indianapolis, Indiana, United States, 46202
United States, Maryland
Research Site
Bethesda, Maryland, United States, 20892
United States, Nevada
Research Site
Las Vegas, Nevada, United States, 89169
United States, South Carolina
Research Site
Charleston, South Carolina, United States, 29424
United States, Tennessee
Research Site
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site
Temple, Texas, United States, 76508
Poland
Research Site
Łódź, Poland, 93-510
Sponsors and Collaborators
MedImmune LLC
Investigators
Study Director: Ramy Ibrahim, M.D. MedImmune LLC

Additional Information:
Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT01030536     History of Changes
Obsolete Identifiers: NCT01086644
Other Study ID Numbers: MI-CP218
First Posted: December 11, 2009    Key Record Dates
Results First Posted: April 9, 2018
Last Update Posted: April 9, 2018
Last Verified: March 2018

Keywords provided by MedImmune LLC:
NHL
CLL

Additional relevant MeSH terms:
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell