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

Phase 2CompletedNCT01994382

Alexion Pharmaceuticals, Inc.260 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

260

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)

Interventions

CerdulatinibDRUG

Oral capsule

RituximabBIOLOGICAL

IV infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (23)

Unnamed facility

Huntsville, Alabama, United States

Unnamed facility

Gilbert, Arizona, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

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

Secondary Outcomes

Data from ClinicalTrials.gov

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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.

Time frame: 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.

Time frame: 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.

Time frame: 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

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)

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.

Time frame: 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.

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

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.

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