Clinical trial NCT01994382: Phase 1/2a Dose Escalation Study in Participants With CLL, SLL, or NHL
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Portola Pharmaceuticals
First posted: 2013-11-25
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Phase 1: Number of Participants With a Dose Limiting Toxicity (DLT)
timeFrame: Baseline up to Day 28 of Cycle 1 (cycle = 21 days or 28 days)
measure: Phase 2a: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])
Secondary outcomes:
measure: Phase 1: Number of Participants Achieving Overall Response Rate (Partial Response [PR] Plus Complete Response [CR]) as Assessed by the Investigator
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days])
measure: Phase 1: Number of Participants Achieving Clinical Benefit
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 21 days or 28 days])
measure: Phase 1 and Phase 2: Number of Participants With an Adverse Event (AE) or a Serious Adverse Event (SAE)
timeFrame: Baseline up to End of Study (up to 30 days after last dose in Cycle 10 [cycle = up to 28 days])
measure: Phase 1: Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Cerdulatinib
timeFrame: 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)
measure: Phase 2a: Median Time to Progression-Free Survival (PFS)
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])
measure: Phase 2a: Number of Participants Achieving Clinical Benefit
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])
measure: Phase 2a: Number of Participants Achieving Dominant Mass Response (DMR)
timeFrame: Baseline up to End of Treatment (up to last day of Cycle 10 [cycle = 28 days])
Other outcomes:
Locations:
city: Huntsville
country: United States
state: Alabama
city: Gilbert
country: United States
state: Arizona
city: Los Angeles
country: United States
state: California
city: Palo Alto
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Gainesville
country: United States
state: Florida
city: Sarasota
country: United States
state: Florida
city: Lawrenceville
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: Baltimore
country: United States
state: Maryland
city: Ann Arbor
country: United States
state: Michigan
city: Hattiesburg
country: United States
state: Mississippi
city: Hackensack
country: United States
state: New Jersey
city: Morristown
country: United States
state: New Jersey
city: New York
country: United States
state: New York
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Arlington
country: United States
state: Texas
city: Lubbock
country: United States
state: Texas
city: Richmond
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Milwaukee
country: United States
state: Wisconsin
Study officials:
affiliation: Portola Pharmaceuticals
name: Portola Study Director
role: STUDY_DIRECTOR
References:
citation: 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
citation: 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.