Principal Investigator: Deborah  Stephens
Keywords: CLL Lymphoma Department: Hematology
IRB Number: 00087788
Specialty: Hematology/BMT
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Deborah  Stephens
lindsay.carpenter@hci.utah.edu
8015874756

Brief Summary

Part 1

PRIMARY OBJECTIVE

To characterize the safety profile of acalabrutinib alone or in combination with rituximab in subjects with R/R FL

SECONDARY OBJECTIVES:

• To characterize the safety profile of acalabrutinib in combination with rituximab in subjects with previously untreated FL

• To characterize the PK profile of acalabrutinib alone or in combination with rituximab

• To evaluate the PD effects of acalabrutinib alone or in combination with rituximab

• To evaluate the activity of acalabrutinib alone or in combination with rituximab as measured by response rate, DOR, time-to-next treatment, and PFS 

Part 2

Primary Objective

• To characterize the activity of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL, as measured by ORR

Secondary Objectives

• To characterize the safety of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL

• To evaluate the activity of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL, as measured by DOR, PFS, and OS

Exploratory Objectives

• To evaluate time-to-next treatment in subjects with R/R MZL treated with acalabrutinib alone or in combination with rituximab

• To evaluate the PD effects of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL

To evaluate MRD negativity rate in subjects with R/R MZL

 

PART 3 AND PART 4

Primary Objective
 To characterize the safety of acalabrutinib in combination with rituximab and lenalidomide in subjects with R/R FL or R/R non-GCB DLBCL

Secondary Objectives:
 To characterize the activity of acalabrutinib in combination with rituximab and lenalidomide in subjects with R/R FL or R/R non-GCB DLBCL as measured by ORR, DOR, PFS, and OS

Exploratory Objectives:
 To evaluate acalabrutinib and its active metabolite (ACP-5862) concentration relative to clinical response and/or progressive disease
 To evaluate the PD effects of acalabrutinib in combination with rituximab and lenalidomide in subjects with R/R FL or R/R non-GCB DLBCL
 To evaluate the molecular profile of tumor, blood, ctDNA, and bone marrow, when available (including but not limited to BTK mutation), in subjects with R/R FL or R/R non-GCB DLBCL
 To evaluate MRD negativity rate in subjects with R/R FL or R/R non-GCB DLBCL
 To evaluate time-to-next treatment in subjects with R/R FL or R/R non-GCB DLBCL

Inclusion Criteria

Inclusion Criteria Part 1

Eligible subjects will be considered for inclusion in this study if they meet all of the following criteria:

1. Men and women ≥18 years of age.

2. Relapsed/Refractory Cohort: A confirmed diagnosis of FL Grade 1, 2, or 3a that has relapsed after, or been refractory to ≥1 prior therapy for FL and which requires treatment per National Cancer Institute or International Working Group guidelines. Documented failure to achieve at least PR with, or documented disease progression
after, the most recent treatment regimen.

Treatment-naive Cohort: A confirmed diagnosis of FL Grade 1, 2, or 3a that requires treatment per National Cancer Institute or International Working Group guidelines in subjects who have not previously received systemic anticancer therapy for FL. 

3. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy as defined by the protocol.

4. ECOG performance status of ≤2.

5. Agreement to use highly effective methods of contraception during the study and for 90 days after the last dose of acalabrutinib or 12 months after the last dose of rituximab, whichever is longer, if sexually active and able to bear or beget children. Highly effective forms of contraception are defined in Section 3.7.6.

6. Men must agree to refrain from sperm donation during the study and for 12 months after the last dose of rituximab.

7. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

Inclusion Criteria Part 2
Eligible subjects will be considered for inclusion in this study if they meet all of the following criteria:

1. Men and women ≥18 years of age.

2. Histologically confirmed MZL including splenic, nodal, and extranodal sub-types, as defined in the protocol

3. Previous therapy:

a. Cohort 1: Previously received 1 or more lines of systemic therapy including at least 1 CD20-directed regimen (either as monotherapy or as chemoimmunotherapy for MZL) with documented failure to achieve at least
PR, or documented disease progression after the most recent treatment regimen.

b. Cohort 2: Previously received 1 or more lines of therapy including at least 1 prior systemic therapy for MZL or radiation therapy with documented failure to achieve at least PR, or document disease progression after the most
recent treatment regimen.

4. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the longest dimension and ≥1.0 cm in the longest perpendicular dimension as assessed by CT scan). Lesions in anatomical locations, such as extremities or soft tissue
lesions, that are not well visualized by CT may be measured by magnetic resonance imaging (MRI) instead; subjects with spleen-only disease are considered as not having measurable disease.

5. ECOG performance status of ≤2.

6. Women must agree to use highly effective methods of contraception during the study and for 2 days after the last dose of acalabrutinib or 12 months after the last dose of rituximab, whichever is longer, if sexually active and able to bear or beget children.
Highly effective methods of contraception are defined in the protocol

7. Men must agree to refrain from sperm donation during the study and for 12 months after the last dose of rituximab.

8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national patient privacy regulations).

Inclusion Criteria Part 3
Eligible subjects will be considered for inclusion in this study if they meet all of the following criteria.

1. Men and women ≥18 years of age.

2. For subjects with FL: Pathologically confirmed diagnosis of FL Grade 1, 2, or 3a that has relapsed after, or been refractory to, ≥1 prior therapy for FL and which requires treatment per National Cancer Institute or European Society for Medical Oncology (ESMO) clinical practice guidelines.

3. This criterion was removed under Amendment 6.

4. Subjects must have previously received at least 1 frontline standard chemoimmunotherapy regimen.

5. Subjects with suspected residual disease after the treatment regimen directly preceding study enrollment must have biopsy-demonstrated residual FL.

6. Documented R/R disease, defined as either: 1) recurrence of disease after a CR or PR, or 2) stable disease or progressive disease at completion of the treatment regimen preceding entry to the study (residual disease).

7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy, as defined in the protocol.

8. ECOG performance status of ≤2.

9. Females of reproductive potential must
a. have 2 negative pregnancy tests prior to initiating treatment with lenalidomide. The first should be within 10 to 14 days and the second test within 24 hours prior to first dose of lenalidomide.
b. must commit to abstain continuously from heterosexual sex or use 2 highly effective methods of contraception. Contraception must be used beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy with any
study drug, and during dose interruptions for lenalidomide. Contraception must be used for 2 days after the last dose of acalabrutinib,12 months after the last dose of rituximab, or 4 weeks after the last dose of lenalidomide, whichever is later.

10. Men must agree to use a synthetic or latex condom during any sexual contact with female of reproductive potential while taking lenalidomide and for up to 4 weeks after last dose of lenalidomide, even if they have undergone a successful vasectomy. Men must agree to refrain from sperm donation during the study and for 12 months after the last dose of rituximab or 4 weeks after the last dose of lenalidomide, whichever is later.

11. Subjects must not donate blood during treatment with lenalidomide and for 4 weeks after discontinuation of lenalidomide.

12. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

13. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national patient privacy regulations).

Exclusion Criteria

Exclusion Criteria Part 1

Subjects will be ineligible for this study if they meet any of the following criteria:

1. Prior malignancy (other than indolent B-cell NHL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥2 years.

2. Known CNS lymphoma or leptomeningeal disease.

3. A life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

4. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

5. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) >480 msec.

6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

7. Any immunotherapy within 4 weeks of first dose of study drug.

8. Relapsed/Refractory Cohort: The time from the last dose of the most recent chemotherapy or experimental therapy to the first dose of study drug is <5 times the half-life of the previously administered agent(s).

9. Prior exposure to a BCR inhibitor (e.g., BTK, phosphonositide-3 kinase [PI3K], or spleen tyrosine kinase [SYK] inhibitors) or BCL-2 inhibitor (e.g., venetoclax).

10. Known history of anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) or any of its components.

11. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment of FL or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤20 mg of prednisone or equivalent) as therapy for comorbid conditions. During study participation, subjects may also receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.

12. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.

13. Known history of HIV or active infection with hepatitis C virus (HCV) or any uncontrolled active systemic infection.

14. Known hepatitis B infection or positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc). Since intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, subjects who are receiving prophylactic IVIG and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to be
eligible.

15. Major surgery within 4 weeks before first dose of acalabrutinib.

16. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

17. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.

18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist (e.g., phenprocoumon) within 7 days of first dose of study drug.

19. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

20. Received a live virus vaccination within 28 days of first dose of study drug.

21. ANC <0.75 × 109/L or platelet count <50 × 109/L. For subjects with documented disease involvement in the bone marrow, ANC <0.50 × 109/L or platelet count <30 × 109/L.

22. Creatinine >2.5 × institutional upper limit of normal (ULN); total bilirubin >2.5 × ULN; and AST or ALT >3.0 × ULN.

23. Breastfeeding or pregnant.

24. Concurrent participation in another therapeutic clinical trial.

25. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening.

Exclusion Criteria Part 2
Subjects will be ineligible for this study if they meet any of the following criteria:

1. Prior malignancy (other than indolent B-cell NHL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥2 years.

2. Known medically apparent CNS lymphoma or leptomeningeal disease.

3. Known evidence of transformation to another aggressive lymphoma.

4. A life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

5. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

6. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia formula
(QTcF) >480 msec.

7. Malabsorption syndrome, disease significantly affecting gastrointestinal function (excluding gastric MALT), or resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

8. This criterion was removed under Amendment 5.

9. This criterion was removed under Amendment 5.

10. Prior exposure to a BCR inhibitor (e.g., BTK, or SYK inhibitors).

11. For Cohort 2, evidence of CD20− MZL and/or known history of anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) or any of its components.

12. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment or other conditions within 1 week before the first dose of study drug.
Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤20 mg of prednisone or equivalent for up to 2 weeks) as therapy for comorbid conditions. However, subjects requiring systemic steroids at daily doses >20 mg prednisone equivalent of systemic exposure are not allowed.

13. Grade ≥2 toxicity (other than alopecia or laboratory value requirements mentioned in Part 2) continuing from prior anticancer therapy including radiation.

14. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug.

15. Known history of infection with HIV.

16. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative hepatitis B virus (HBV) DNA polymerase chain reaction (PCR) result before enrollment. Subjects who are HBsAg positive or
hepatitis B PCR positive will be excluded.
b. Subjects who are anti-HCV positive will need to have a negative PCR result before enrollment. Subjects who are hepatitis C PCR positive will be excluded.

17. History of allogeneic stem cell (or organ) transplantation.

18. This criterion was removed under Amendment 5.

19. Major surgery within 4 weeks before first dose of acalabrutinib.

20. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

21. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.

22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist (e.g., phenprocoumon) within 7 days of first dose of study drug.

23. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

24. Received a live virus vaccination within 28 days of first dose of study drug.

25. ANC <1.0 × 109/L or platelet count <100 × 109/L. For subjects with documented disease involvement in the bone marrow, ANC <0.50 × 109/L or platelet count <30 × 109/L.

26. Creatinine >1.5 × institutional ULN; total bilirubin >1.5 × ULN; and AST or ALT >2.5 × ULN.

27. Breastfeeding or pregnant.

28. Concurrent participation in another therapeutic clinical trial.

29. In the absence of gastric MALT (subject to inclusion criterion 2b) presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening or diagnosed >3 months before screening and without confirmed resolution by endoscopy.

30. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.

31. History of or ongoing progressive multifocal leukoencephalopathy (PML).

Exclusion Criteria Part 3
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥2 years.

2. Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.

3. Known history or presence of CNS lymphoma or leptomeningeal disease.

4. Transformed DLBCL or DLBCL with coexistent histologies (e.g., FL or mucosa-associated lymphoid tissue and primary mediastinal large B-cell lymphoma [PMBCL]).

5. A life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of acalabrutinib or lenalidomide, or put the study outcomes at undue risk.

6. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

7. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTcF >480 msec. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to be enrolled on study.

8. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

9. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.

10. Prior exposure to a BCR inhibitor (e.g., BTK or SYK inhibitors), lenalidomide, or CAR-T cell therapy.

11. Known history of anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) or any of its components.

12. Subjects with a prior history of Grade 4 rash associated with thalidomide treatment.

13. Ongoing immunosuppressive therapy, including systemic (e.g., IV or oral) corticosteroids within 2 weeks before the first dose of study drug. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤20 mg prednisone equivalent/day for ≤2 weeks) as a therapy for comorbid conditions. During study participation, subjects may also receive systemic (e.g., IV or oral) corticosteroids as needed for treatment-emergent comorbid conditions.

14. Grade ≥2 toxicity (other than alopecia or laboratory value requirements mentioned in Part 3 exclusion criteria) continuing from prior anticancer therapy including radiation.

15. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs or symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug.

16. Known history of infection with HIV.

17. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before enrollment. Subjects who are HBsAg positive or hepatitis B PCR positive will be excluded.
b. Subjects who are HCV antibody (anti-HCV) positive will need to have a negative PCR result before enrollment. Subjects who are HCV PCR positive will be excluded.

18. History of allogeneic stem cell (or organ) transplantation.

19. Major surgery within 4 weeks before first dose of acalabrutinib.

20. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

21. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.

22. Requires or has received anticoagulation with warfarin or equivalent vitamin K antagonist (e.g., phenprocoumon) within 7 days of first dose of study drug.

23. Received a live virus vaccination within 28 days of first dose of study drug.

24. ANC <1.0 × 109/L or platelet count <75 × 109/L. Subjects will only be considered eligible if peripheral blood counts can be maintained independent of growth factors or transfusions during screening.

25. Creatinine clearance of <60 mL/min, as defined in the protocol. 

26. Total bilirubin >1.5 × ULN, or AST or ALT >2.5 × ULN, unless directly attributable to Gilbert’s syndrome.

27. Requires treatment with a strong CYP3a inhibitor/inducer.

28. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subject receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.

29. Breastfeeding or pregnant.

30. Concurrent participation in another therapeutic clinical trial.

31. History of or ongoing PML.