Clinical trial NCT03527147: Platform Study for the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma (PRISM Study)
Official title: PRISM: A Platform Protocol for the Treatment of Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: NHL
DLBCL
Non-hodgkin's Lymphoma
Diffuse Large B Cell Lymphoma
Keywords: Acalabrutinib
CALQUENCE®
ACP-196
Platform study
Master protocol
PRISM
Hu-5F9
Rituximab
ATR
STAT3
Anti-CD47
BRD4
Lead sponsor: Acerta Pharma BV
Sponsor class: INDUSTRY
Collaborators: name: AstraZeneca
First posted: 2018-05-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1 platform protocol designed to evaluate various targeted agents for the treatment of relapsed/refractory aggressive Non-Hodgkin's Lymphoma (NHL).

Detailed description: This is a Phase 1 platform protocol designed to evaluate various targeted agents for the treatment of relapsed/refractory aggressive Non-Hodgkin's lymphoma (NHL). Each study arm will be conducted in a predefined disease subset. All study arms are open label and allocation to each study arm will not be randomized.

As this master platform protocol has multiple study arms, subjects can be screened for several study arms at once. Likewise, a subject who ends participation in one study arm may be rescreened for participation in another (separate) study arm.

The primary objective of the study is to evaluate the safety of targeted agents for the treatment of relapsed/refractory aggressive Non-Hodgkin's Lymphoma (NHL). This protocol has a modular design, with the potential for future treatment arms to be added via protocol amendment.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria For All Arms:

1. Diagnosis of relapsed/refractory aggressive Non Hodgkin's Lymphoma (NHL) with histology based on established World Health Organization (WHO) criteria.
2. Must have received ≥1 prior line of therapy for the treatment of current histology, there are no known curative treatment options available, or subject ineligible for potential curative options.
3. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy. Not applicable for cutaneous lesions.
4. ECOG performance status of ≤2.

Inclusion Criteria for Arm 1:

1. Must have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone or equivalent regimen with stem-cell rescue. Or who are ineligible for highdose chemotherapy with stem-cell rescue and/or chimeric antigen receptor (CAR) T cell therapy.

Ineligibility for high-dose therapy with stem cell rescue and/or CAR T-cell therapy will be determined by the investigator.

Inclusion Criteria for Arm 2:

1. Must have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone or equivalent regimen with stem-cell rescue. Or who are ineligible for highdose chemotherapy with stem-cell rescue and/or chimeric antigen receptor (CAR) T-cell therapy.

Ineligibility for high-dose therapy with stem cell rescue and/or CAR T-cell therapy will be determined by the investigator.

Inclusion Criteria for Arm 3:

1. Must have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone or equivalent regimen with stem-cell rescue. Or who are ineligible for highdose chemotherapy with stem-cell rescue and/or chimeric antigen receptor (CAR) T cell therapy.

Ineligibility for high-dose therapy with stem cell rescue and/or CAR T-cell therapy will be determined by the investigator.

Inclusion Criteria for Arm 4:

1. Must have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone or equivalent regimen with stem-cell rescue. Or who are ineligible for highdose chemotherapy with stem-cell rescue and/or chimeric antigen receptor (CAR) T cell therapy.

Ineligibility for high-dose therapy with stem cell rescue and/or CAR T-cell therapy will be determined by the investigator.

Exclusion Criteria:

Exclusion Criteria For All Arms:

1. History of prior malignancy except for the following: a) Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician, b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer, c) Adequately treated carcinoma in situ without current evidence of disease, d) Evidence of severe or uncontrolled systemic disease, or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses or uncontrolled active systemic fungal, bacterial, viral, or other infection, or intravenous anti-infective treatment within 2 weeks before first dose of study treatment.
2. Serologic status reflecting active hepatitis B or C infection.
3. Prior use of standard antilymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment (not including palliative radiotherapy or palliative corticosteroid use).
4. Requires ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid cancer or other conditions.
5. For subjects under DLT review only: Any haematopoietic growth factors or darbepoetin within 14 days of the first dose of study treatment.

Exclusion Criteria for Arm 1:

1. Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
2. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
3. Requires treatment with proton-pump inhibitors.
4. Requires treatment with strong CYP3A inhibitors or inducers.

Exclusion Criteria for Arm 2:

1. Relative hypotension (\< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of \>20 mm Hg.
2. Uncontrolled hypertension requiring clinical intervention.
3. At risk for brain perfusion problems based on medical history.
4. Mean resting QT interval (QTc) calculated using Fridericia's formula (QTcF) \>470 msec for female subjects and \>450 msec for male subjects obtained from 3 electrocardiograms (ECGs), or congenital long QT syndrome.
5. Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
6. Known to have tested positive for human immunodeficiency virus (HIV) \& requires treatment with restricted medications.
7. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
8. Requires treatment with proton-pump inhibitors.

Exclusion Criteria for Arm 3:

1. Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
2. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
3. Requires treatment with proton-pump inhibitors.
4. Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of RBC transfusions during the 4-week period prior to screening.
5. History of haemolytic anaemia or Evans syndrome in the last 3 months before enrolment.
6. Positive IgG component of the direct antiglobulin test (DAT).
7. Prior treatment with CD47 or SIRPα-targeting agents.
8. Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab

Exclusion Criteria for Arm 4:

1. Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
2. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
3. Requires treatment with proton-pump inhibitors.
4. Requires treatment with CYP3A inhibitors or inducers or substrates of drug transporters.
5. History of tuberculosis.
6. Mean resting corrected QT interval (QTcF) \>450 msec obtained from 3 electrocardiograms (ECGs); clinically important ECG findings, or risk factors for QTc prolongation.
7. Subjects receiving antiplatelet or anticoagulant therapies within 28 days of first dose of study drug.

Primary outcomes:
measure: Safety of the study treatments when given in combination [Incidence of adverse events]
timeFrame: Through to study completion, an average of 1 year
Secondary outcomes:
measure: Assessment of the efficacy of each treatment by evaluation of overall response rate using RECIL 2017 response criteria
timeFrame: Through to study completion, an average of 1 year
measure: Duration of response (DOR) using RECIL 2017 response criteria for the anti-tumour activity of each therapy.
timeFrame: Through to study completion, an average of 1 year
measure: Progression free survival (PFS) using RECIL 2017 response criteria for the anti-tumour activity of each therapy.
timeFrame: Through to study completion, an average of 1 year
measure: Overall Survival (OS)
timeFrame: From the beginning of treatment until the date of death from any cause, assessed up to 12 months
measure: Peak plasma concentration (Cmax) of Study Drug A (Arm 1)
timeFrame: Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only; then predose and approximately 1 hr (end of infusion of Study Drug A) on Day 1 of every odd cycle starting with Cycle 3 through study completion, an average of 1 year
measure: Peak plasma concentration (Cmax) of Study Drug B (Arm 2)
timeFrame: Samples will be collected predose and 1, 4, 8 hours postdose on Cycle 1 Day 8 only; then predose on Cycle 2 Day 1 and Cycle 3 Day 1
measure: Area under the plasma concentration versus time curve (AUC) of Study Drug A (Arm 1)
timeFrame: Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only; then predose and approximately 1 hr (end of infusion of Study Drug A) on Day 1 of every odd cycle starting with Cycle 3 through study completion, an average of 1 year
measure: Area under the plasma concentration versus time curve (AUC) of Study Drug B (Arm 2)
timeFrame: Samples will be collected predose and 1, 4, 8 hours postdose on Cycle 1 Day 8 only; then predose on Cycle 2 Day 1 and Cycle 3 Day 1
measure: Presence of Anti-Drug Antibody (ADA) titres in subjects treated with Study Drug A
timeFrame: Samples will be collected predose on Days 1 and 8 of Cycle 1 and predose on Day 1 of every odd cycle starting with Cycle 3
measure: Peak plasma concentration (Cmax) of acalabrutinib (Arm 1)
timeFrame: Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only
measure: Area under the plasma concentration versus time curve (AUC) for acalabrutinib (Arm 1)
timeFrame: Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only
measure: Peak plasma concentration (Cmax) of acalabrutinib (Arm 2)
timeFrame: Samples will be collected predose and 1, 4, 8 hours postdose on Cycle 1 Day 8 only; then predose on Cycle 2 Day 1 and Cycle 3 Day 1
measure: Area under the plasma concentration versus time curve (AUC) for acalabrutinib (Arm 2)
timeFrame: Samples will be collected predose and 1, 4, 8 hours postdose on Cycle 1 Day 8 only; then predose on Cycle 2 Day 1 and Cycle 3 Day 1
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Sarasota
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: New Orleans
country: United States
facility: Research Site
state: Louisiana
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Rochester
country: United States
facility: Research Site
state: New York
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Charlottesville
country: United States
facility: Research Site
state: Virginia
city: Seattle
country: United States
facility: Research Site
state: Washington
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Tennessee Oncology
name: Ian Flinn, MD, PhD
role: STUDY_CHAIR
References: