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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1/2 Study of CAT-8015 in Adult Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

Conditions
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Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAT-8015 20 microgram per kilogram (mcg/kg)<br>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<br>* 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.<br>|
| Experimental: CAT-8015 30 mcg/kg<br>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<br>* 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.<br>|
| Experimental: CAT-8015 40 mcg/kg<br>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<br>* 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.<br>|
| Experimental: CAT-8015 50 mcg/kg<br>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<br>* 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.<br>|
| Experimental: CAT-8015 60 mcg/kg<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | 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. | Day 1 to end of Cycle 1 (approximately 28 days) | 
| Number of Participants With Dose Limiting Toxicities (DLTs) | 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. | Day 1 to end of Cycle 1 (approximately 28 days) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | 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. | From Screening (Day -28) to Post Therapy Day 30 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) | 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. | From Screening (Day -28) to Post Therapy Day 30 | 
| Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) | 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. | From Screening (Day -28) to Post Therapy Day 30 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) | 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. | From Screening (Day -28) to Post Therapy Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) | The CR rate was defined as the percentage of participants who had achieved CR based on both the evaluable population for efficacy. | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Duration of Complete Response | 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. | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Percentage of Participants With Partial Response (PR) |  | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Percentage of Participants With Objective Response (OR) | OR was defined as the percentage of participants with CR or partial response (PR). | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Time to Response (TTR) | 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). | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Duration of Objective Response (DOR) | DOR was measured from the first documentation of OR to the event of relapse. DOR was calculated using the Kaplan-Meier method. | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Duration of Stable Disease (SD) | 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. | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 
| Maximum Plasma Concentration (Cmax) of Moxetumomab Pasudotox | Maximum observed drug concentration of Moxetumomab pasudotox in plasma. | 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 Concentration-Time Curve From Dosing Extrapolated to Infinity (AUCinf) of Moxetumomab Pasudotox | Area under the concentration versus time curve from zero to infinity (AUC) of Moxetumomab pasudotox in Plasma. | 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 | 
| Clearance (CL) of Moxetumomab Pasudotox | CL of drug is rate at which drug is metabolized or eliminated by normal biological processes and is influenced by fraction of dose absorbed. | 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 | 
| Elimination Half Life (t1/2) of Moxetumomab Pasudotox | Plasma decay half life is the time measured for the plasma concentration to decrease by one half. | 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 | 
| Number of Participants With Positive Anti-Drug Antibody | The moxetumomab pasudotox specific bridging assay using the Meso Scale Discovery platform was employed to detect anti-drug antibodies (ADA). | Baseline (Day 1) up to End of the Treatment (Last dose of Last cycle) (approximately 3 years) | 
| Number of Participants With CD22 Expression Levels | 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. | Baseline (Day 1) up to End of the Treatment (Last dose of Last cycle) (approximately 3 years) | 
| Number of Capillary Leak Syndrome (CLS) Participants With Weight Changes, Albumin, Hypotension, Edema, Hypoxia, and Pulmonary Adverse Events (AEs) | The correlation of CLS and weight changes, albumin, hypotension, edema, hypoxia, and pulmonary AEs were examined. | From Screening (Day -28) to Post Therapy Day 30 | 
| Percentage of Participants With Stable Disease (SD) |  | Baseline (Day 1) until Final Study Visit Post Therapy (up to 2 year after the last participant begins study drug treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, CLL