Inclusion Criteria:

Part 1

• Diagnosis of non-GCB DLBCL or iNHL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO).
  • If a subject has DLBCL, it is characterized as de novo non-GCB DLBCL (Choi 2009 or Hans 2004).
  • If the subject has iNHL, the histology shows 1 of the following subtypes:
    •  FL Grade 1, 2, or 3a;
    •  CLL/SLL.
• Prior treatment for lymphoid malignancy (applies to Part 1 and Part 2):
  • If the subject has DLBCL, there is no curative option with conventional therapy and the prior treatment included ≥ 1 prior combination chemoimmunotherapy regimen (eg, anthracycline based therapy with rituximab).
  • If the subject has MCL or iNHL, the prior treatment comprised any of the following:
    •  ≥ 1 regimen containing an anti-CD20 antibody administered for ≥ 2 doses, and/or
    •  ≥ 1 regimen containing ≥ 1 cytotoxic agent (eg, bendamustine, chlorambucil, cyclophosphamide, cytarabine, doxorubicin) administered for ≥ 2 cycles, and/or
    •  ≥ 1 regimen containing yttrium90-ibritumomab tiuxetan (ZEVALIN®) or iodine131-tositumomab (BEXXAR®).
• Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of a ≥ 2.0 cm lesion, as measured in the longest dimension by computed tomography [CT] scan). Note: Not applicable to subjects with WM and MM.
• ANC ≥ 1.5 x 109/L or platelet count ≥ 100 x 109/L unless due to disease involvement in the bone marrow (Part 1 only).

Part 2

• ANC ≥ 0.5 x 109/L and platelet count ≥ 50 x 109/L unless due to disease involvement in the bone marrow (Part 2 only).

Additional Part 2 disease entry criteria including those listed in Part 1 above:

• DLBCL (GCB): Confirmed diagnosis of DLBCL with disease characterized as GCB subtype by immunohistochemistry (Choi 2009 or Hans 2004) and meeting the rest of the criteria as defined above, including characterization as de novo LBCL.
• If the subject has MCL, it is characterized by documentation of monoclonal B-cell that have a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1.
• Richter’s syndrome: Confirmed diagnosis of and biopsy-proven DLBCL due to Richter transformation and meeting the rest of the criteria as defined above.
• MM: Confirmed diagnosis of MM, which has relapsed after, or been refractory to ≥ 3 prior therapies for MM, and is progressing at the time of study entry and meeting the rest of the criteria as defined above. Must be able to provide archival or newly obtained bone marrow aspirate/biopsy material for biomarker analysis.
• WM: Confirmed diagnosis of WM, which has relapsed after, or been refractory to ≥ 1 prior therapy for WM, and is progressing at the time of study entry and meeting the rest of the criteria as defined above. Must be able to provide archival or newly obtained bone marrow aspirate/biopsy material for biomarker analysis.
• Other B-cell malignancy (including but not limited to: Hodgkin’s lymphoma, Burkitt lymphoma, marginal zone lymphomas, mediastinal large B-cell lymphoma, and hairy cell leukemia):
  • Confirmed diagnosis of previously treated B-cell malignancy and meeting the rest of the criteria as defined above.

Part 3 (Under Amendment 3 of this protocol, Part 3 is closed to enrollment)

• Diagnosis of primary MF, post-polycythemia vera MF, or postessential thrombocythemia MF.
• Intermediate-1, intermediate-2, or high-risk MF per Passamonti 2010 criteria and must have failed therapy with ruxolitinib.
• Thrombocytopenia (platelet count ≤ 100 x 109/L at any time after signing informed consent) OR anemia (hemoglobin ≤ 8.0 g/dL).  Subjects who are platelet or red blood cell transfusion-dependent are eligible; platelet counts must be ≥ 30 x 109/L during the screening period.
• Palpable splenomegaly ≥ 5 cm on physical examination.
• Total Symptom Score ≥ 13 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF TSS), not including the inactivity question.
• No splenic irradiation within 6 months before first study dose.
• No myelofibrosis therapy, including any erythropoietic or thrombopoietic agents, within 2 weeks before first study dose.
• ANC ≥ 0.5 x 109/L. 
• Bone marrow blasts < 10%.

All Parts

• Men and women ≥ 18 years of age on day of signing informed consent.
• Documented active disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Completion of all therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥ 4 weeks before the start of study therapy (Parts 1 and 2) and recovered (ie, Grade ≤ 1 or baseline) from AEs associated with prior cancer therapy (all subjects).
  • Note:  Subjects with Grade ≤ 2 neuropathy or Grade ≤ 2 alopecia are an exception to the latter criterion and may qualify for the study.
• Women who are sexually active and can bear children must agree to use highly effective methods of contraception during the study and for 90 days after the last dose of acalabrutinib or 120 days after the last dose of pembrolizumab, whichever is longer.
  • Note: Highly effective methods of contraception are defined in Section 3.10.7.
• Men who are sexually active and can beget children must agree to use highly effective methods of contraception during the study and for 90 days after the last dose of acalabrutinib or 120 days after the last dose of pembrolizumab, whichever is longer. Highly effective methods of contraception are defined in Section 3.10.7.
• Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of acalabrutinib or 120 days after the last dose of pembrolizumab, whichever is longer.
• Able to provide tissue, if available, from either an archived or newly obtained tumor sample (most recent biopsy) for biomarker and correlative analysis as appropriate for a given histology. 
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
• 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).

Exclusion Criteria - All Parts:

• 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.
• 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.
• 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 at screening.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or 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. 
• Central nervous system (CNS) involvement by lymphoma/leukemia
• Any therapeutic antibody within 4 weeks of first dose of study drug.
• Any prior irreversible BTK inhibitor therapy. Note: Prior treatment with reversible, noncovalent BTK inhibitors is not excluded on this protocol.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) antibody (including ipilimumab, tremelimumab, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Receiving ongoing immunosuppressive therapy, including systemic or enteric corticosteroids except for minimally systemically absorbed treatments (such as inhaled or topical steroid therapy for asthma, chronic obstructive pulmonary disease, or allergic rhinitis) within 7 days before the first dose of pembrolizumab.
• Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents,corticosteroids or immunosuppressive drugs).
  • Note:  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• History of interstitial lung disease or non-infectious pneumonitis that required steroids or current pneumonitis.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• History of bleeding diathesis (eg, hemophilia or von Willebrand disease).
• Prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
• Requires treatment with a strong CYP3A inhibitor/inducer.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
• Requires treatment with a proton-pump inhibitor (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.
• Major surgery within 28 days of first dose of study drug.
  • Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 
• Has received a live vaccine within 30 days of planned start of study therapy.
• History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug.
• Active bleeding that requires hospitalization during the screening period.
• Total bilirubin > 1.5 x institutional upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN.
• Estimated creatinine clearance of < 30 mL/min, calculated using the formula of Cockcroft and Gault [(140-Age):
  • Mass (kg)/(72 creatinine mg/dL); multiply by 0.85 if female].
• Breastfeeding or pregnant or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
• Is currently participating in a clinical trial and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Immediate family members of the sponsor personnel or site staff directly involved with the conduct of this protocol are excluded from participating on this study.
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
• Active or known tuberculosis infection.
  • Note: Tuberculosis testing is not required for this protocol.
• Serologic status reflecting active hepatitis B or C infection:
  • Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded.
  • Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment.  Those who are hepatitis C PCR positive will be excluded.