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Phase 1/2a Dose Escalation Study in Participants With CLL, SLL, or NHL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01994382
Recruitment Status : Completed
First Posted : November 25, 2013
Results First Posted : April 5, 2022
Last Update Posted : April 5, 2022
Sponsor:
Collaborator:
Portola Pharmaceuticals
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Brief Summary:
This study will identify the highest dose, and assess the safety, of cerdulatinib (PRT062070) that may be given in participants with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or non-hodgkin lymphoma.

Condition or disease Intervention/treatment Phase
Follicular Lymphoma (FL/Indolent NHL) Aggressive NHL (a NHL) Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL) T-cell Lymphoma (PTCL and CTCL) B-cell Non Hodgkin Lymphoma (NHL) Drug: Cerdulatinib Biological: Rituximab Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

This is an open-label, Phase 1/2a, multi-dose, multi-center trial of orally administered cerdulatinib assessing safety, tolerability, and pharmacokinetic (PK) parameters conducted in 2 phases:

  • Phase 1: Dose-escalation portion, during which participants will be enrolled to receive a single-agent cerdulatinib at their assigned dose level starting at 15 milligrams (mg) once daily (QD), administered in increasing doses until the maximum tolerated dose (MTD)/maximum administered dose (MAD) is identified.
  • Phase 2a: Consisting of planned cohorts based on cancer type. The participants will receive single agent cerdulatinib at a starting dose of 35, 30, or 20 mg twice daily (BID) for 28-day cycles except for one of the cohorts, the participants will receive cerdulatinib plus intravenous (IV) rituximab at 375 mg/square meter (m^2) for 28-day cycles.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 260 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a Open-Label, Multi-Dose, Multi-Center Escalation and Exploratory Study of Cerdulatinib (PRT062070) in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) or B-Cell or T-Cell Non-Hodgkin Lymphoma (NHL)
Actual Study Start Date : August 30, 2013
Actual Primary Completion Date : December 15, 2020
Actual Study Completion Date : December 15, 2020


Arm Intervention/treatment
Experimental: Phase 1 Cerdulatinib
During Phase 1, participants will receive oral cerdulatinib on Day 1 and then starting on Day 4 at doses of 15 mg up to 100 mg QD or oral cerdulatinib at doses of 15 mg up to 45 mg BID in 28-day cycles (except Cohort 1 will have a 21-day cycle starting on Day 1) for up to 10 cycles.
Drug: Cerdulatinib
Oral capsule
Other Names:
  • PRT062070
  • ALXN2075

Experimental: Phase 2a Cerdulatinib
During Phase 2a, participants in cohorts based on cancer type will receive oral cerdulatinib at starting doses of 35, 30, or 20 mg BID on Day 1 in 28-day cycles for up to 10 cycles. Doses of cerdulatinib can be reduced to a minimum dose of 15 mg BID or increased to a maximum dose of 30 mg BID at the discretion of the Investigator based upon clinical judgment and with Sponsor Medical Monitor approval.
Drug: Cerdulatinib
Oral capsule
Other Names:
  • PRT062070
  • ALXN2075

Experimental: Phase 2a Cerdulatinib plus Rituximab
During Phase 2a, participants in this cohort will receive oral cerdulatinib at their applicable dose and an IV injection of rituximab 375 mg/m^2 on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 4, 6, 8, and 10.
Drug: Cerdulatinib
Oral capsule
Other Names:
  • PRT062070
  • ALXN2075

Biological: Rituximab
IV infusion
Other Names:
  • Rituxan®
  • Truxima®
  • Rixathon®
  • Ruxience®
  • MabThera®




Primary Outcome Measures :
  1. Phase 1: Number of Participants With a Dose Limiting Toxicity (DLT) [ Time Frame: Baseline up to Day 28 of Cycle 1 (cycle = 21 days or 28 days) ]
    DLT was defined as any of the following toxicities, possibly or probably related to cerdulatinib, and clinically significant (in the judgement of Investigator): -Febrile neutropenia (absolute neutrophil count <1000/microliter [μL] and temperature ≥38.5°Celcius). -Grade 4 neutropenia for >5 days. -Grade 4 thrombocytopenia with or without bleeding. -Grade 3 thrombocytopenia with bleeding. -Grade 4 anemia, unexplained by underlying disease. -Grade 3 or greater nausea, vomiting, or diarrhea if persistent despite optimal antiemetic or anti-diarrheal therapy. -Grade 3 or greater increase in transaminases lasting >5 days. -Grade 3 or greater fatigue persisting >7 days in absence of any other underlying cause. -Any other Grade 3 or greater non-hematologic toxicity (except fatigue as noted above) considered clinically significant by Investigator. -Toxicity of any grade resulting in dose delay of >7 days. -Toxicity resulting in study drug discontinuation prior to completion of Cycle 1.

  2. Phase 2a: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) ]

    CR included: -Via a positron emission tomography (PET)/computed tomography (CT) scan, score of 1 (no uptake above background), 2 (uptake of <mediastinum), or 3 (uptake of >mediastinum but <liver) for lymph nodes and extralymphatic sites; no new lesions; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. -Via CT scan, target nodes/nodal masses regressed to <1.5 centimeters (cm) in longest transverse diameter of a lesion (LDi); no extralymphatic sites of disease; organ enlargement has regressed to normal; and bone marrow was normal by morphology and if indeterminate, immunohistochemistry was negative.

    PR included: -Via a PET/CT scan, score of 4 (uptake of moderately >liver) or 5 (uptake markedly higher than liver and/or new lesions) with reduced uptake compared with baseline and residual masses of any size. -Via CT scan, >50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites.



Secondary Outcome Measures :
  1. Phase 1: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days]) ]

    CR included: -Via a PET/CT scan, score of 1 (no uptake above background), 2 (uptake of <mediastinum), or 3 (uptake of >mediastinum but <liver) for lymph nodes and extralymphatic sites; no new lesions; and no evidence of FDG-avid disease in bone marrow. -Via CT scan, target nodes/nodal masses regressed to <1.5 cm in LDi; no extralymphatic sites of disease; organ enlargement has regressed to normal; and bone marrow was normal by morphology and if indeterminate, immunohistochemistry was negative.

    PR included: -Via a PET/CT scan, a score of 4 (uptake of moderately >liver) or 5 (uptake markedly higher than liver and/or new lesions) with reduced uptake compared with baseline and residual masses of any size. -Via CT scan, >50% decrease in the sum of the product of perpendicular diameters for multiple lesion of up to 6 target measurable nodes and extranodal sites.


  2. Phase 1: Number of Participants Achieving Clinical Benefit [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days]) ]
    Clinical benefit was defined as achieving stable disease (SD) or better, as assessed by the Investigator. SD included: -Via a PET/CT scan, a score of 4 (uptake of moderately >liver) or 5 (uptake markedly higher than liver and/or new lesions) with no significant change in FDG uptake from baseline at interim or end of treatment; no new lesions; and no change from baseline in bone marrow. -Via CT scan, <50% decrease from baseline in sum of products of the greatest perpendicular diameters (SPD) of up to 6 dominant, measurable nodes and extranodal sites; no increase consistent with progression in nonmeasured lesions or organ enlargement; and no new lesions.

  3. Phase 1 and Phase 2: Number of Participants With an Adverse Event (AE) or a Serious Adverse Event (SAE) [ Time Frame: Baseline up to End of Study (up to 30 days after last dose in Cycle 10 [cycle = up to 28 days]) ]
    An AE is any untoward medical occurrence, which may or may not have a causal relationship to the study drug, including: unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug; any newly occurring event or exacerbation of previous condition (for example, increase in severity or frequency) since the administration of study drug; recurrence of an intermittent medical condition not present at baseline; any deterioration in a laboratory value or other clinical test that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study drug; and AEs related to a study intervention. An SAE is an AE that is fatal, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect.

  4. Phase 1: Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Cerdulatinib [ Time Frame: Cycle (C)1 Day (D)1: predose (0), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, and 72 hours postdose (except 15mg QD); C1D1: 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose (15mg QD); C2D1: 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose (all doses) ]
  5. Phase 2a: Median Time to Progression-Free Survival (PFS) [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) ]
    PFS=(first documentation of disease progression [DP] or death [whichever occurred first]-study drug first dose date+1)/30.4375 in months. PFS right censored for 1 of these conditions: 1) no baseline disease assessments; 2) starting new anticancer therapy before documented DP/death; 3) DP/death immediately after >6 months since last disease assessment (or >12 months if after last cycle); & alive without documented DP. 95% confidence interval estimated using Brookmeyer method. DP included: -Via a PET/CT scan, score of 4 (uptake of moderately >liver) or 5 (uptake markedly higher than liver and/or new lesions) with uptake increase in intensity, new FDG-avid foci, & no nonmeasured lesions. -Via CT, abnormal individual node/lesion with significant LDi or shortest axis perpendicular to LDi increase; prior splenomegaly, >50% splenic length increase; if no prior splenomegaly, ≥2 cm splenic length increase; new or recurrent splenomegaly; new/clear progression of preexisting nonmeasured lesions.

  6. Phase 2a: Number of Participants Achieving Clinical Benefit [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) ]
    Clinical benefit was defined as achieving SD or better, as assessed by the Investigator. SD included: -Via a PET/CT scan, a score of 4 (uptake of moderately >liver) or 5 (uptake markedly higher than liver and/or new lesions) with no significant change in FDG uptake from baseline at interim or end of treatment; no new lesions; and no change from baseline in bone marrow. -Via CT scan, <50% decrease from baseline in sum of products of the greatest perpendicular diameters (SPD) of up to 6 dominant, measurable nodes and extranodal sites; no increase consistent with progression in nonmeasured lesions or organ enlargement; and no new lesions.

  7. Phase 2a: Number of Participants Achieving Dominant Mass Response (DMR) [ Time Frame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) ]
    DMR was defined as achieving a ≥50% decrease from baseline in the SPD of the target nodal and extranodal lesions. SPD at a visit was considered missing if any target lesion was not evaluated.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Phase 1 Inclusion

• Participant at least 18 years of age with histologically confirmed CLL/SLL or B-cell non-Hodgkin lymphoma (diffuse large B-cell lymphoma [DLBCL], FL, mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma).

Phase 2a Inclusion

  • Histological evidence: FL Grade 1-3A, with relapsed or refractory disease; aggressive NHL (aNHL), defined as DLBCL, FL Grade 3B, MCL, and transformed NHL with relapsed disease; CLL/SLL, peripheral T-cell lymphoma (PTCL), or cutaneous T-cell lymphoma (CTCL) (with mycosis fungoides [MF]/Sézary Syndrome [SS]) with relapsed or refractory disease
  • Received B-cell receptor (BCR) and/or BCL2 inhibitors and were intolerant or had relapsed/refractory disease afterwards
  • Prior treatment for lymphoid malignancy for progressive /refractory disease
  • ≥1 prior regimen (minimum 2 cycles) with antibody conjugate/cytotoxic chemotherapy.
  • Measurable disease defined as: ≥1 lesion that measures ≥1.5 centimeter (cm) single dimension via computed tomography (CT), CT/positive-emission tomography (PET) with nodal or mass lesions; quantifiable circulating tumor cells; and for CTCL: Modified Severity Weighted Assessment Tool (mSWAT) >0
  • Ability to provide diagnostic reports

General Inclusion

  • Eastern Cooperative Oncology Group (ECOG) Score of 0 or 1
  • Hematologic absolute neutrophil count (ANC) >1000/microliter (uL) and platelet >75,000/uL
  • Creatinine levels as specified by Investigator
  • Bilirubin <2.0 mg/deciliter [dL] (if Gilberts then <2.5 mg/dL) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <2.5*ULN

Exclusion Criteria:

  • Richter's syndrome, Burkitt's lymphoma, or Burkitt-like Lymphoma (transformed DLBCL from follicular NHL are eligible)
  • Prior transplant with stem cell infusion within 90 days of Day 1 or active graft-versus-host treatment within 8 weeks of Day 1
  • Prior therapy with Spleen Tyrosine Kinase (SYK) inhibitors
  • Chronic treatment with strong CYP3A4 inhibitor/inducer
  • Known lymphomatous involvement of the central nervous system (CNS)
  • Persistent, unresolved National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 ≥Grade 2, previous drug-related toxicity (except alopecia, erectile impotence, hot flashes, libido, neuropathy).
  • Prior monoclonal antibody (including alemtuzumab), radioimmunoconjugate, antibody drug conjugate, phototherapy, radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any test agent within 3 weeks of Day 1
  • For CTCL: (total skin electron beam therapy [TSEBT]) within 12 weeks, or initiation of topical steroid, nitrogen mustard, or topical retinoid within 2 weeks. Stable topical regimen for ≥4 weeks prior to Day 1 allowed.
  • Known carrier or infection for human immunodeficiency virus (HIV)/hepatitis B or C. If hepatitis C virus (HCV) antibody (ab)+, must be polymerase chain reaction (PCR)- to be eligible. If hepatitis B virus (HBV) ab+, must be hepatitis B surface antigen (HBsAg)- or undetectable HBV deoxyribonucleic acid (DNA) to be eligible.
  • Active infection requiring systemic treatment,
  • Significant gastrointestinal (GI) disease, previous major gastric/bowel surgery, difficulty swallowing, or malabsorption syndrome
  • Major surgery within 4 weeks
  • Previous malignancies within 2 years unless relapse risk is small (<5%).
  • Current use of systemic steroids >20 mg QD prednisone (or equivalent)
  • Breastfeeding or pregnant (intention to become) females or participation in other clinical trials

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): NCT01994382


Locations
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United States, Alabama
Huntsville, Alabama, United States, 35805
United States, Arizona
Gilbert, Arizona, United States, 85234
United States, California
Los Angeles, California, United States, 90095
Palo Alto, California, United States, 94304
United States, District of Columbia
Washington, District of Columbia, United States, 20007
United States, Florida
Gainesville, Florida, United States, 32608
Sarasota, Florida, United States, 34232
United States, Georgia
Lawrenceville, Georgia, United States, 30046
United States, Illinois
Chicago, Illinois, United States, 60637
United States, Kentucky
Louisville, Kentucky, United States, 40207
United States, Maryland
Baltimore, Maryland, United States, 21229
United States, Michigan
Ann Arbor, Michigan, United States, 48109
United States, Mississippi
Hattiesburg, Mississippi, United States, 39402
United States, New Jersey
Hackensack, New Jersey, United States, 07601
Morristown, New Jersey, United States, 07960
United States, New York
New York, New York, United States, 10021
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Charleston, South Carolina, United States, 29412
United States, Texas
Arlington, Texas, United States, 76012
Lubbock, Texas, United States, 79410
United States, Virginia
Richmond, Virginia, United States, 23226
United States, Washington
Seattle, Washington, United States, 98109
United States, Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Alexion Pharmaceuticals
Portola Pharmaceuticals
Investigators
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Study Director: Portola Study Director Portola Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:
Study Protocol  [PDF] October 14, 2019
Statistical Analysis Plan  [PDF] November 17, 2020

Publications of Results:
Paul A. Hamlin, Manish R. Patel, Don Stevens, Brian T. Hess, Javier Munoz, Tatyana A. Feldman, Sonali M. Smith, Greg P. Coffey, Muhtarjan Osman, Jaymes S Holland, Cristina B Guzman, Stephen D. Smith; Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy or in Combination with Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma. Blood 2021; 138 (Supplement 1): 2423. doi: https://doi.org/10.1182/blood-2021-148313

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01994382    
Other Study ID Numbers: 13-601
First Posted: November 25, 2013    Key Record Dates
Results First Posted: April 5, 2022
Last Update Posted: April 5, 2022
Last Verified: April 2022
Keywords provided by Alexion Pharmaceuticals:
Leukemia
Lymphocytic
Chronic
B Cell
Additional relevant MeSH terms:
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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
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents