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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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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)

Intervention / Treatment
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* Drug: Cerdulatinib
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Cerdulatinib<br>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<br>* Oral capsule<br>* Other names: ALXN2075;|
| Experimental: Phase 2a Cerdulatinib<br>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<br>* Oral capsule<br>* Other names: ALXN2075;|
| Experimental: Phase 2a Cerdulatinib plus Rituximab<br>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<br>* Oral capsule<br>* Other names: ALXN2075;Biological: Rituximab<br>* IV infusion<br>* Other names: MabThera®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a: Number of Participants Achieving Dominant Mass Response (DMR) | 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. | Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) | 
| Phase 1: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator | 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. | 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 | 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. | 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) | 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. | 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) | 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. | Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) | 
| Phase 2a: Number of Participants Achieving Clinical Benefit | 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. | Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Lymphocytic, Chronic, B Cell