A Phase 1/2 Study of CYT-0851 in B-Cell Malignancies and Advanced Solid Tumors

Key Phase 1 Inclusion Criteria

   1. Male or female ≥18 years of age at time of informed consent.

      1. Female subjects of childbearing potential must be non-lactating, not pregnant as
      confirmed by a negative serum pregnancy test at most 30 days before enrollment
      and within 72 hours before the first administration of CYT-0851

      2. Female subjects of childbearing potential must not donate ova during the study
      and for at least 90 days after the last dose of study drug and must agree to
      continue using an effective method of contraception during the screening period
      to first study drug administration until 90 days after the last dose of study
      drug

      3. Male subjects who have not had a vasectomy must agree to use an effective method
      of contraception during the study and until 90 days after the last dose of the
      study drug, and to not donate sperm during the study and for at least 90 days
      after the last dose of study drug

   2. ECOG Performance Status of 0-1

   3. Measurable disease defined by disease-specific response criteria

   4. Histologically-proven B cell malignancies, meeting the following criteria:

      1. Relapsed, refractory B-cell non-Hodgkin lymphoma requiring therapy, after at
      least two prior therapies, and if transplanted, then at least 3-month post
      autologous stem cell transplant and if CART-treated, then evidence of progression
      no sooner than 3 months post CART treatment, or

      2. Relapsed, refractory chronic lymphocytic leukemia requiring therapy after at
      least two prior therapies, including BTK and BCL-2 inhibitor therapy (unless
      ineligible for such therapy), or

      3. For multiple myeloma, relapsed or progressive on or after treatment with at least
      three prior therapies that included a proteasome inhibitor, an imide,
      daratumumab, and if transplant eligible, a bone marrow transplant (unless unfit
      for transplant), or

   5. Histologically-proven solid tumor meeting the following criteria:

      1. Patients must have failed, refused, or not be eligible for further standard
      therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies,
      as appropriate) expected to provide clinical benefit, and meeting the following
      criteria

      2. Metastatic breast cancer (including ER/PR positive or negative, Her-2 positive
      and negative, triple negative), treated with at least 1 prior therapy for
      metastatic disease, or

      3. Recurrent squamous cell carcinoma of the head and neck (HNSCC) (dose escalation)
      or human papilloma virus positive (HPV+) HNSCC (dose-escalation and backfill),
      treated with at least 1 prior therapy, or

      4. Ovarian cancer, progressive after treatment with at least prior platinum-based
      chemotherapy, and therapy with a PARP inhibitor or

      5. Soft tissue sarcoma, treated with at least one line of prior systemic therapy, or

      6. Recurrent metastatic or locally advanced pancreatic cancer after first line
      chemotherapy (backfill or combination patients only) or

      7. Histologically-proven advanced small-cell lung cancer (SCLC) (monotherapy
      backfill patients only).

         1. Patients with mixed histology are not allowed

         2. Prior treatment with platinum containing chemotherapy regimen with no
         evidence of progression within 90 days of last dose of platinum agent and
         anti-PD-(L)1 unless contraindicated

         3. At least 1 prior line of chemotherapy, but no more than 3 prior lines of
         therapy

   6. Understands the procedures and requirements of the study and provides written informed
   consent and authorization for protected health information disclosure

   7. Willing and able to comply with the requirements of the study protocol

   8. Site of disease amenable to a biopsy and willing to undergo biopsy required for
   backfill, or for dose-escalation if considered unsafe (approval to participate in the
   study required by the Medical Monitor) provide an archival sample ≤ 12 months old

Key Phase 2 Inclusion Criteria

   1. Male or female ≥18 years of age at time of informed consent.

      1. Female subjects of childbearing potential must be non-lactating, not pregnant as
      confirmed by a negative serum pregnancy test at most 30 days before enrollment
      and within 72 hours before the first administration of CYT-0851

      2. Female subjects of childbearing potential must not donate ova during the study
      and for at least 90 days after the last dose of study drug and must agree to
      continue using, an effective method of contraception during the screening period
      to first study drug administration until 90 days after the last dose of study
      drug

      3. Male subjects who have not had a vasectomy must agree to use an effective method
      of contraception during the study and until 90 days after the last dose of the
      study drug, and to not donate sperm during the study and for at least 90 days
      after the last dose of study drug

   2. ECOG Performance Status of 0-1

   3. Measurable disease defined by disease-specific response criteria

   4. Site of disease amenable to a biopsy and willing to undergo a biopsy for the
   determination of biomarker status, or, if considered unsafe (approval to participate
   in the study required by the Medical Monitor), archival sample ≤ 12 months old for
   determination of biomarker status.

   5. Biomarker positive on recent biopsy or bone marrow sample if required for the specific
   cohort.

   6. Histologically-proven B cell malignancies, meeting the following criteria:

      1. DLBCL Cohort

         1. Histologically-documented DLBCL or double hit lymphoma (B-cell lymphoma,
         unclassifiable, with features intermediate between diffuse large B-cell
         lymphoma and Burkitt lymphoma with BCL2 and MYC translocations (WHO
         Classification)

         2. Progressing on or after treatment with at least two prior lines of therapy,
         including R-CHOP or equivalent first line therapy

         3. If transplanted, then at least 3-month post autologous stem cell transplant

         4. If CART-treated, then evidence of progression no sooner than 3 months post
         CART treatment

      2. MCL Cohort

         1. Histologically-documented MCL

         2. Any stage at diagnosis

         3. Progressing on or after treatment with at least 2 prior lines of therapy,
         including a Bruton tyrosine kinase (BTK) inhibitor, after a 14-day washout
         period

      3. Multiple Myeloma Cohort

         1. Relapsed or progressing after treatment with at least 3 prior therapies that
         include a proteasome inhibitor, an Immunomodulatory imide drug (IMiD),
         daratumumab, and, if transplant eligible, a bone marrow transplant (unless
         unfit for transplant)

   7. Or Histologically-proven solid tumors meeting the following criterial

      1. Patients must have failed, refused, or not be eligible for further standard
      therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies,
      as appropriate) expected to provide clinical benefit, and meeting the following
      criteria

      2. Triple Negative Breast Cancer Cohort

         1. Histologically-documented triple negative breast cancer, ER/PR negative
         (defined as <10% of cells expressing hormonal receptors via
         immunohistochemistry (IHC) analysis), and HER2-negative, defined as either
         of the following by local laboratory assessment:

            - In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0
            or single probe average HER2 gene copy number < 4 signals/cell), or

            - IHC 0 or IHC 1+

         2. At least 1 prior line of chemotherapy, but no more than 5 prior lines of
         chemotherapy

      3. Ovarian Cancer Cohort

         1. Histologically-proven metastatic epithelial ovarian cancer

         2. Prior treatment with a platinum containing chemotherapy regimen

         3. At least 1 prior line of therapy, but no more than 5 prior lines of
         chemotherapy

      4. Pancreatic Cancer Cohort

         1. Histologically-proven metastatic or locally advanced pancreatic cancer

         2. At least 1 prior line of chemotherapy but no more than 4 prior lines of
         systemic therapy

      5. Soft Tissue Sarcoma Cohort 1) Histologically-proven advanced soft-tissue sarcoma
      excluding all types of adipocytic sarcoma and GIST 2) At least 1 prior line of
      systemic therapy (unless no standard of care exists), but no more than 5 prior
      lines of systemic therapy

   8. Follicular Lymphoma Cohort

      1. Histologically-documented follicular lymphoma

      2. Relapsed, refractory follicular lymphoma requiring therapy, after at least two
      prior therapies, and if CART-treated, then evidence of progression no sooner than
      3 months post CART treatment

   9. Understands the procedures and requirements of the study and provides written informed
   consent and authorization for protected health information disclosure

10. Willing and able to comply with the requirements of the study protocol

Key Exclusion Criteria

   1. Medical Conditions

      1. Known history of HIV

      2. Known history of viral hepatitis B unless HBV viral load is below the limit of
      quantification and off viral suppressive therapy

      3. Know history of hepatitis C unless antiviral treatment with curative intent
      completed and HCV viral load is below the limit of quantification.

      4. Myocardial infarction or stroke within 6 months

      5. Uncontrolled hypertension (systolic blood pressure (SBP) > 160 or diastolic blood
      pressure (DBP) >100 on maximal medical therapy)

      6. History of interstitial pulmonary disease

      7. Unresolved pneumonitis

      8. Grade ≥ 3 neuropathy

      9. Known active central nervous system (CNS) metastases. Subjects with previously
      treated CNS metastases may participate as long as clinically and radiologically
      stable for at least 4 weeks after treatment, have no evidence of new or enlarging
      lesions and are off steroids and asymptomatic for 28 days prior to dosing with
      study medication

   10. Known history of meningeal involvement or meningeal carcinomatosis

   11. Spinal cord compression not definitively treated with surgery and/or radiation,
      or previously diagnosed and treated spinal cord compression without evidence that
      disease has been clinically stable for > 2 weeks prior to screening visit

   12. Presence of clinically significant cataracts

   13. Second malignancy, except treated basal cell or localized squamous skin
      carcinomas, localized prostate cancer, or other malignancy that is in remission
      or stable and for which patients have not been on active anti-cancer therapy for
      2 years

   14. Pregnant or lactating. If β-HCG is elevated, eligible if ultrasound confirms
      absence of a pregnancy.

   15. Dementia or significantly altered metal status

   16. Bowel obstruction requiring medical management less than 4 weeks prior to
      screening

   17. Inability to tolerate oral intake that includes 2 full meals per day (or
      equivalent) or swallow pills.

   18. Recurrent ascites requiring paracentesis more frequently than every 4 weeks or
      within 14 days of screening.

   19. Weight loss of more than 10% over the preceding 3 months prior to screening

   2. Prior/Concomitant Therapy

      1. Prior allogeneic stem cell transplant

      2. On systemic antibiotic, antifungal or anti-viral therapy

      3. White blood cell (WBC) growth factors administered within 14 days of screening
      visit

      4. Cancer therapy within 14 days prior to treatment with study drug

      5. On narrow therapeutic index medications that are sensitive substrates of CYP3A,
      P-gp or BCRP (or caution is warranted with approval by the Sponsor).

      6. On any drug known to prolong QTc interval (eg, certain antiarrhythmic,
      antimicrobials) that cannot be discontinued or interrupted 72 hours before the
      Day 1 dose through Day 2, and 72 hours before the Day 15 dose until Day 16 (BID
      dosing) or the Day 22 dose until Day 23 (QD dosing), in Cycle 1 (see Section
      7.6.1 for a list of drugs).

      7. On systemic corticosteroid treatment for non-tumor indication at a daily dose
      equivalent to >10mg of Prednisone

   3. Prior/Concurrent Clinical Study Experience a. Participation in another clinical trial
   (unless in the observation phase, or an observational study), or exposure to any
   investigational agent within 14 days prior to treatment with study drug

   4. Laboratory assessments

      1. Complete blood count (CBC):

      Monotherapy and Chemotherapy Combinations 1 and 2:

         1. ANC < 1.0 × 10^9/L

         2. PLT < 75 × 10^9/L

         3. Hgb < 9.0 g/dL

         Chemotherapy Combination Group 3:

      1) ANC < 1.5 × 10^9/L 2) PLT < 100 × 10^9/L 3) Hgb < 9.0 g/dL

      Monotherapy and Chemotherapy Combination Groups 1 and 2:

      2. Calculated Creatinine clearance (Cockcroft-Gault) < 40 mL/min

Chemotherapy Combination Group 3:

b. Calculated Creatinine clearance (Cockcroft-Gault) < 50 mL/min c. Hepatic function

   1. AST > 2.0 × ULN

   2. ALT > 2.0 × ULN d. Total bilirubin > 1.5 x ULN e. Albumin < 2.8 g/dL 5. ECG Exclusion
   a. Screening QTc interval > 450 milliseconds for males and QTc > 470 ms for females
   (corrected by Fridericia) 6. Other Exclusions

      1. Unwilling or unable to make all planned study visits

      2. Unwilling or unable to provide a recent biopsy or bone marrow sample prior to
      enrollment and during study; Note: certain exceptions may be permitted allowing
      archival specimens prior to treatment or for subjects where a specimen is not
      required for biomarker positive testing

      3. Significant medical diseases or conditions, as assessed by the Investigators and
      Cyteir that would substantially increase the risk-benefit ratio of participating
      in the study. This includes but is not limited to acute myocardial infarction,
      arterial thrombosis, significant gastrointestinal bleed, or unstable angina
      within the last 6 months uncontrolled diabetes mellitus, current active
      infections, severely immunocompromised state, and congestive heart failure New
      York Heart Association (NYHA) Class III-IV, left ventricular ejection fraction
      (LVEF) < 40% d: Chemotherapy Combination Group 3 only: known history of
      dhydropyrimidine dehydrogenase deficiency