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

NCT01994382 | Completed Phase 1 Results

• 1 other identifier: 13-601
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 23

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.

Conditions

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)

Keywords

Leukemia; Lymphocytic; Chronic; B Cell

Outcome Measures

Primary Outcomes (2)

• Phase 1: Number of Participants With a Dose Limiting Toxicity (DLT)

  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.

  Baseline up to Day 28 of Cycle 1 (cycle = 21 days or 28 days)

• Phase 2a: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator

  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.

  Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])

Secondary Outcomes (7)

• Phase 1: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator

  Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days])

• Phase 1: Number of Participants Achieving Clinical Benefit

  Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days])

• Phase 1 and Phase 2: Number of Participants With an Adverse Event (AE) or a Serious Adverse Event (SAE)

  Baseline up to End of Study (up to 30 days after last dose in Cycle 10 [cycle = up to 28 days])

• Phase 1: Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Cerdulatinib

  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)

• Phase 2a: Median Time to Progression-Free Survival (PFS)

  Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])

Study Arms (3)

Phase 1 Cerdulatinib

EXPERIMENTAL

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

Phase 2a Cerdulatinib

EXPERIMENTAL

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

Phase 2a Cerdulatinib plus Rituximab

EXPERIMENTAL

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; Biological: Rituximab

Interventions

Cerdulatinib DRUG

Oral capsule

Also known as: PRT062070, ALXN2075

Phase 1 Cerdulatinib; Phase 2a Cerdulatinib; Phase 2a Cerdulatinib plus Rituximab

Rituximab BIOLOGICAL

IV infusion

Also known as: Rituxan®, Truxima®, Rixathon®, Ruxience®, MabThera®

Phase 2a Cerdulatinib plus Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead
• Portola Pharmaceuticals: collaborator

Study Sites (23)

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Huntsville, Alabama, 35805, United States

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Gilbert, Arizona, 85234, United States

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Los Angeles, California, 90095, United States

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Palo Alto, California, 94304, United States

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Washington D.C., District of Columbia, 20007, United States

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Gainesville, Florida, 32608, United States

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Sarasota, Florida, 34232, United States

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Lawrenceville, Georgia, 30046, United States

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Chicago, Illinois, 60637, United States

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Louisville, Kentucky, 40207, United States

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Baltimore, Maryland, 21229, United States

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Ann Arbor, Michigan, 48109, United States

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Hattiesburg, Mississippi, 39402, United States

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Hackensack, New Jersey, 07601, United States

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Morristown, New Jersey, 07960, United States

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New York, New York, 10021, United States

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Philadelphia, Pennsylvania, 19104, United States

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Charleston, South Carolina, 29412, United States

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Arlington, Texas, 76012, United States

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Lubbock, Texas, 79410, United States

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Richmond, Virginia, 23226, United States

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Seattle, Washington, 98109, United States

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Milwaukee, Wisconsin, 53226, United States

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Related Publications (2)

• 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

  RESULT

• Coffey GP, Feng J, Betz A, Pandey A, Birrell M, Leeds JM, Der K, Kadri S, Lu P, Segal J, Wang YL, Michelson G, Curnutte JT, Conley PB. Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies. Clin Cancer Res. 2019 Feb 15;25(4):1174-1184. doi: 10.1158/1078-0432.CCR-18-1047. Epub 2018 Oct 17.

  PMID: 30333224 DERIVED

MeSH Terms

Conditions

Lymphoma, Follicular; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Lymphoma, B-Cell; Leukemia; Bronchiolitis Obliterans Syndrome

Interventions

4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Key limitations of the study included that it was originally a single-arm, short-term study; disease progression was included as an AE; inadequate follow-up for death or progression; a lack of use of antimicrobial prophylaxis; and no uniform gastrointestinal toxicity management algorithm. These limitations impacted dose reduction and discontinuations due to treatment emergent AEs. In addition, monitoring issues due to the COVID-19 pandemic also factored into data collection and verification.

Results Point of Contact

• Title: Alexion Pharmaceuticals, Inc.
• Organization: Alexion Pharmaceuticals, Inc.

clinicaltrials@alexion.com

+1.855.752.2356

Study Officials

• Portola Study Director

  Portola Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 8, 2013
• First Posted: November 25, 2013
• Study Start: August 30, 2013
• Primary Completion: December 15, 2020
• Study Completion: December 15, 2020
• Last Updated: April 5, 2022
• Results First Posted: April 5, 2022

Record last verified: 2022-04

Locations

US (23)