Platform Study for the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma (PRISM Study)
Study Details
Study Description
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: AZD9150 + Acalabrutinib AZD9150 given in combination with acalabrutinib |
Drug: AZD9150
AZD9150 will be administered as a 1-hour intravenous (IV) infusion on Days 1, 3, 5 of Cycle 1, followed by weekly infusions (starting Day 8 of Cycle 1 and beyond).
Other Names:
Drug: Acalabrutinib
Acalabrutinib will be administered orally twice daily (bid).
Other Names:
|
Experimental: AZD6738 + Acalabrutinib AZD6738 in combination with acalabrutinib |
Drug: Acalabrutinib
Acalabrutinib will be administered orally twice daily (bid).
Other Names:
Drug: AZD6738
AZD6738 will be administered orally twice daily (bid).
Other Names:
|
Experimental: Hu5F9-G4 + rituximab + Acalabrutinib Hu5F9-G4/rituximab in combination with acalabrutinib |
Drug: Acalabrutinib
Acalabrutinib will be administered orally twice daily (bid).
Other Names:
Drug: Hu5F9-G4
HU5F9-G4 infusions will be given on Weekly (Day 1, 8, 15, and 22) during the first two 28-day cycles, then will be given every two weeks (Day 1 and Day 15) in Cycle 3 and beyond.
Other Names:
Drug: Rituximab
Rituximab infusions will be given Weekly starting on Day 8 (Day 8, 15, and 22) during the first 28-day cycle (4 weeks), then Day 1 of each 4 week cycle for Cycles 2-6. Starting with Cycle 8, Rituximab will be infused on Day 1 of every other cycle (every 8 weeks).
Other Names:
|
Experimental: AZD5153 + Acalabrutinib AZD5153 in combination with acalabrutinib |
Drug: Acalabrutinib
Acalabrutinib will be administered orally twice daily (bid).
Other Names:
Drug: AZD5153
AZD5153 will be administered orally once per day (qd).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Safety of the study treatments when given in combination [Incidence of adverse events] [Through to study completion, an average of 1 year]
Incidence of adverse events
Secondary Outcome Measures
- Assessment of the efficacy of each treatment by evaluation of overall response rate using RECIL 2017 response criteria [Through to study completion, an average of 1 year]
The overall response rate (ORR) is defined as the rate of subjects who achieve either a partial response (PR) or complete response (CR) as assessed by investigators before receiving any other anticancer therapy.
- Duration of response (DOR) using RECIL 2017 response criteria for the anti-tumour activity of each therapy. [Through to study completion, an average of 1 year]
Duration of Response (DOR) is defined as the time from the first objective response of CR or PR to the time of documented disease progression or death due to any cause, whichever occurs first.
- Progression free survival (PFS) using RECIL 2017 response criteria for the anti-tumour activity of each therapy. [Through to study completion, an average of 1 year]
Progression free survival (PFS) is defined as the time from first dose date to documented objective disease progression, or death from any cause, whichever occurs first. Disease progression will be determined by the investigators per standard response criteria as outlined in each respective study arm.
- Overall Survival (OS) [From the beginning of treatment until the date of death from any cause, assessed up to 12 months]
Overall Survival (OS) is defined as the time from first dose until the date of death from any cause.
- Peak plasma concentration (Cmax) of Study Drug A (Arm 1) [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]
- Peak plasma concentration (Cmax) of Study Drug B (Arm 2) [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]
- Area under the plasma concentration versus time curve (AUC) of Study Drug A (Arm 1) [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]
- Area under the plasma concentration versus time curve (AUC) of Study Drug B (Arm 2) [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]
- Presence of Anti-Drug Antibody (ADA) titres in subjects treated with Study Drug A [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]
- Peak plasma concentration (Cmax) of acalabrutinib (Arm 1) [Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only]
- Area under the plasma concentration versus time curve (AUC) for acalabrutinib (Arm 1) [Samples will be collected predose and 1, 4, 6 hours postdose on Cycle 1 Day 8 only]
- Peak plasma concentration (Cmax) of acalabrutinib (Arm 2) [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]
- Area under the plasma concentration versus time curve (AUC) for acalabrutinib (Arm 2) [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]
Eligibility Criteria
Criteria
Inclusion Criteria:
Inclusion Criteria For All Arms:
-
Diagnosis of relapsed/refractory aggressive Non Hodgkin's Lymphoma (NHL) with histology based on established World Health Organization (WHO) criteria.
-
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.
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Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy. Not applicable for cutaneous lesions.
-
ECOG performance status of ≤2.
Inclusion Criteria for Arm 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:
- 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:
- 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:
- 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:
-
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.
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Serologic status reflecting active hepatitis B or C infection.
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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).
-
Requires ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid cancer or other conditions.
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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:
-
Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
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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.
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Requires treatment with proton-pump inhibitors.
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Requires treatment with strong CYP3A inhibitors or inducers.
Exclusion Criteria for Arm 2:
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Relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of >20 mm Hg.
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Uncontrolled hypertension requiring clinical intervention.
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At risk for brain perfusion problems based on medical history.
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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.
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Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
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Known to have tested positive for human immunodeficiency virus (HIV) & requires treatment with restricted medications.
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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.
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Requires treatment with proton-pump inhibitors.
Exclusion Criteria for Arm 3:
-
Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
-
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.
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Requires treatment with proton-pump inhibitors.
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Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of RBC transfusions during the 4-week period prior to screening.
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History of haemolytic anaemia or Evans syndrome in the last 3 months before enrolment.
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Positive IgG component of the direct antiglobulin test (DAT).
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Prior treatment with CD47 or SIRPα-targeting agents.
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Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab
Exclusion Criteria for Arm 4:
-
Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.
-
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.
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Requires treatment with proton-pump inhibitors.
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Requires treatment with CYP3A inhibitors or inducers or substrates of drug transporters.
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History of tuberculosis.
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Mean resting corrected QT interval (QTcF) >450 msec obtained from 3 electrocardiograms (ECGs); clinically important ECG findings, or risk factors for QTc prolongation.
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Subjects receiving antiplatelet or anticoagulant therapies within 28 days of first dose of study drug.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Research Site | Los Angeles | California | United States | 90095 |
2 | Research Site | Sarasota | Florida | United States | 34232 |
3 | Research Site | Atlanta | Georgia | United States | 30322 |
4 | Research Site | New Orleans | Louisiana | United States | 70112 |
5 | Research Site | Bethesda | Maryland | United States | 20892 |
6 | Research Site | Omaha | Nebraska | United States | 68198 |
7 | Research Site | Rochester | New York | United States | 14642 |
8 | Research Site | Nashville | Tennessee | United States | 37203 |
9 | Research Site | Charlottesville | Virginia | United States | 22908 |
10 | Research Site | Seattle | Washington | United States | 98104 |
11 | Research Site | London | United Kingdom | W1G 6AD | |
12 | Research Site | Oxford | United Kingdom | OX3 7EJ |
Sponsors and Collaborators
- Acerta Pharma BV
- AstraZeneca
Investigators
- Study Chair: Ian Flinn, MD, PhD, Tennessee Oncology
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- ACE-LY-111
- 2017-004191-63
- D9820C00001
- LYM 138