Inclusion Criteria:

Phase 1a Escalation (Completed and now Closed)

• Histologically documented, advanced lymphoma after the failure of at least 2 prior therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy.
• Adequate hematologic status (in the absence of transfusion and growth factor support for at least 28 days), defined as:
  • absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
  • platelets ≥ 75 x 109/L;
  • hemoglobin ≥ 10 g/dL.

Phase 1b Expansion (Selected Cohorts Currently Open for Parts 2 and 3)

• Advanced measurable malignancy documented by histology, cytology, flow cytometry, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) methodology in one of the following categories:
  • (closed) Small cell lung cancer (SCLC) (measurable disease by the Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1).
  • Histologically documented, advanced lymphoma after the failure of at least 2 prior systemic therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with CD20-positive NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy:
    • Indolent B-cell lymphoma;
    • Aggressive B-cell lymphoma;
    • Classic Hodgkin lymphoma.
      • Patients with cHL should have failed at least one checkpoint inhibitor therapy before enrolling to the nivolumab combination cohort.　
    • Peripheral T-cell lymphoma ([PTCL] as defined by mature T- and NK-cell neoplasms per WHO and CTCL), having failed at least 1 prior systemic therapy. Subjects with PTCL must have at least 1 site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis).
    • CTCL (both MF and SS):
      • Failed at least 2 prior systemic therapies for CTCL. Systemic therapy does not include local radiation therapy or topical agents;
      • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
      • History of histologically-documented diagnosis of CTCL stage IIB to IVB (Olsen, 2011).
    • (closed) B-cell or T-cell acute lymphoblastic leukemia (ALL):
      • First or greater bone marrow relapse from complete remission; or
      • Any bone marrow relapse after allogeneic transplant; or
      • Absence of complete remission after 2 induction attempts employing standard regimens; or
      • Ph+ B-ALL if subjects are intolerant to or ineligible to receive tyrosine kinase inhibitor therapy or have progressed after at least one line of this therapy.
    • (closed) CLL: subjects should have failed at least 2 prior therapies, including CD20-targeted therapy.
    • (closed) Multiple myeloma (MM): subjects should have failed at least 3 prior therapies, including an immunomodulatory drug (IMID) and proteasome inhibitor-based therapy and have measurable disease as defined as 1 or more of the following:
      • serum M-protein > 0.5g/dl; and/or
      • urine M-protein > 200 mg/24 hours; and/or
      • in subjects who do not meet these criteria, serum free light chains (FLC) > 100 mg/L (involved light chain) and abnormal ratio (FLC kappa/FLC lambda);
      • biopsy-proven plasmacytoma.
    • (closed) AML, with the exception of AML M3 using the French American British (FAB) classification (i.e., acute promyelocytic leukemia [APL]).
    • (closed) MDS of WHO classifications RAEB-1 (refractory anemia with excess blasts) and RAEB-2.
    • (closed) BCR/ABL1-negative myeloproliferative neoplasm (MPN) or myeloproliferative/myelodysplastic overlap neoplasm (MPN/MDS) per the revised 2016 WHO criteria, including:
      • chronic phase (CP) (defined as peripheral blood and bone marrow <10% blasts) primary myelofibrosis or post-essential;
        • if the diagnosis is Myelofibrosis-CP, must have Dynamic International Prognostic Scoring System (DIPSS) intermediate-2/high risk disease (Passamonti et al., 2010) and either be: 1) intolerant/resistant to ruxolitinib or 2) ineligible for ruxolitinib therapy, as determined by the treating Investigator.
      • accelerated phase/blast phase MPN (MPN-AP/BP) (defined as either a peripheral blood or bone marrow with ≥10% blasts);
        • if the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment with a DNA methyl transferase 1 (DNMT1) inhibitor therapy (e.g. azacitidine or decitabine), as determined by the treating Investigator.
      • chronic myelomonocytic leukemia (CMML) -1 or 2 characterized by:
        • > 1x109/L monocytes and 2-19% blasts in peripheral blood or Auer rods; and
        • dysplasia in ≥1hematopoietic line and 5-19% marrow blasts or Auer rods.
      • (closed) Subjects with MPN or MPN/MDS must not be eligible to proceed with hematopoietic stem cell transplantation (HSCT) and must have:
        • for MPN, an indication to treat with cytoreductive drugs (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.), according to the judgment of the treating physician;
        • for MPN, documentation of inadequate response or intolerance to first line therapy, which includes at least one cytoreductive drug (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.);
        • for CMML, documentation of inadequate response or intolerance to first line therapy, which includes at least one hypomethylating agent.
• Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
  • o ANC ≥1 x 109/L (not applicable to subjects with AML, ALL, MDS, or MPN/MDS);
  • o platelets ≥75 x 109/L (≥0 x 109/L if the patient has bone marrow involvement);
  • o hemoglobin ≥9 g/dL.

Phase 1b Expansion (Dose Optimization Part 4)

• Histologically confirmed diagnosis of CTCL (both Mycosis Fungoides and Sezary Syndrome):
  • Failed at least 2 prior systemic therapies for CTCL (systemic therapy does not include local radiation therapy or topical agents);
  • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
  • History of histologically-documented diagnosis of CTCL stage IB to IVB (Olsen, 2011).
• Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
  • ANC ≥ 1 x 109/L;
  • platelets ≥ 75 x 109/L;
  • hemoglobin ≥ 9 g/dL.

Both Phases

• Male or female 18 years of age or older.
• Availability of fresh or archived tumor tissue for immunohistochemical studies. Archival tissue may be used provided it was obtained subsequent to the last prior anti-cancer therapy. For subjects with SS, peripheral blood is acceptable.
• Relapsed or refractory disease that has previously progressed on, or is currently progressing on standard anticancer therapy or for whom no other approved conventional therapy exists.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Adequate coagulation function, defined as:
  • International Normalized Ratio (INR) < 1.5 x the upper limit of normal (ULN) for that laboratory;
  • partial thromboplastin time < 1.5 x ULN;
  • subjects receiving anticoagulation therapy must be on a stable dose with monitoring studies within therapeutic range per local institutional standards
• Adequate hepatic function, defined as:
  • total bilirubin < 1.5 x ULN unless considered due to Gilbert’s disease;
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 1.5 x ULN or < 3 x ULN with documented liver metastases.
• Adequate renal function, defined as estimated serum creatinine clearance > 30 mL/minute calculated using the Cockcroft-Gault equation.
• Recovery from the toxicities of previous anticancer drugs or radiotherapy to Grade 0 or 1 (or to baseline grade if condition was pre-existing).
• Commitment from male and female subjects of reproductive potential to use, from the time of screening through 60 days after the last dose of TTI-621, either:
  • one highly effective method of contraception, including hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants), intrauterine device (IUD) or intrauterine system (IUS), vasectomy, or tubal ligation; OR
  • at least 2 effective methods of contraception, including male condom, female condom, cervical cap, diaphragm, or contraceptive sponge; OR
  • abstain from sex during study participation and for 60 days after the last dose of TTI-621.

Exclusion Criteria:

Both Phases

• (AML cohort closed) AML M3 by FAB classification (APL).
• Known, current central nervous system disease involvement or untreated brain metastases.
• Investigational agent or any anticancer drug within 14 days prior to planned start of treatment (with the exception of hydroxyurea in subjects with MPN, MPN/MDS, ALL or AML).
• Allogeneic transplant within 30 days prior to the planned start of treatment or subjects with active graft-vs-host disease with the exception of Grade 1 skin involvement.
• Prior anti-CD47 therapy, with the exception of prior TTI-621 therapy delivered intratumorally only.
• Major surgery within 28 days prior to planned start of treatment.
• Use of irreversible antiplatelet/anticoagulant agents within 7 days prior to planned start of treatment (except subjects with thrombocytosis where low dose aspirin is being used to reduce the risk of thrombosis); use of low dose aspirin (≤81 mg/day) and selected, reversible anticoagulants are permitted (low molecular weight heparin, heparin, warfarin and dabigatran).
• History of hemolytic anemia or bleeding diathesis.
• Uncontrolled infection requiring systemic antibiotics/antivirals/antifungals.
• Chronic use of systemic corticosteroids of more than 20 mg per day of prednisone or equivalent; enrollment of post-transplant subjects who are on corticosteroids for graft-vs-host disease prophylaxis requires approval of the Medical Monitor. CTCL patients who are on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to study entry may continue its use on study at the same dose.
• Known hypersensitivity to any component of study drug.
• Positive serum pregnancy test in females of child-bearing potential or current breastfeeding.
• Significant cardiovascular disease such as symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic coronary artery disease, myocardial infarction within the last 6 months, unstable arrhythmia requiring treatment, unstable angina, or prolonged QTc interval > 480 milliseconds (Grade 2 or higher) (QTc interval calculation at the discretion of the Investigator).
• Active hepatitis B or C or a history of HIV infection.
• Other significant medical condition unrelated to the primary malignancy that would compromise subject’s safety or ability to comply with protocol requirements.
• Inability for the subject to complete protocol requirements, such as geographic considerations, psychiatric disorders, or other compliance concerns.
• Prior Grade 4 rituximab infusion-related reaction (rituximab combination arm only).
• Active autoimmune disease or history of autoimmune disease that might recur (nivolumab combination arm only); subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.