Overview

A Phase I, Open Label, Dose-Escalation, First in Human (FIH) study evaluating the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AUR103 Calcium in patients with relapsed advanced malignancies (BHARAT-1).

Eligibility

Inclusion Criteria:

1. Provide signed and dated informed consent and agree to comply with all study related activities.
2. Male or female patients aged ≥ 18 years.
3. Patients have to meet the following criteria for each of the respective parts of the

   study

Part 1:

             Pathological diagnosis of a solid tumor. Standard curative or life prolonging measures
             do not exist and patient must have exhausted all effective therapies, available
             locally. At a minimum, patients should have received at least 2 lines of therapy in
             the metastatic setting.
             Part 2A and 2B:
             Diagnosis of Acute myeloid leukemia (AML) according to the World Health Organization
             (WHO 2016, Appendix B) criteria. OR Myelodysplastic syndrome (MDS) according to the
             WHO classification (WHO 2016, Appendix B). Patients with relapsed / refractory AML
             (patients should have received at least one line of previous therapy and be eligible
             for single agent Azacitidine) or Intermediate / High-Risk / Very High-Risk
             Myelodysplastic syndrome (MDS) with IPSS-R score greater than 3.5, by IPSS - R
             criterion (Appendix C) who are eligible to receive AZA.
             Part 3A and 3B:
             Patients of CD20+ B cell NHL, who are refractory or relapsed after at least two
             previous lines of therapy Patients must not have any curative or life prolonging
             option and must not require immediate cytoreductive therapy Patients with histological
             sub-types of follicular lymphoma, marginal zone lymphoma (includes nodal marginal
             zone, splenic marginal zone and extra-nodal marginal zone of MALT tissue), mantle cell
             lymphoma, diffuse large B cell lymphoma, histologically transformed indolent lymphomas
             to DLBCL, high-grade B cell lymphomas and Primary Mediastinal Large B cell Lymphoma.
             Patients with indolent lymphomas (e.g., follicular lymphoma, marginal zone lymphoma or
             mantle cell lymphoma) must have conventional criterion, such as GELF criterion14
             , for requiring treatment Single agent Rituximab is a viable treatment alternative for
             the patient. Please refer to Appendix F for a detailed list of drugs/previous
             treatments. Note: The list is not exhaustive and not every treatment may be available
             locally.
             Patients with respective NHL subtypes should have received the following treatments
             Sub-Type of CD20+ B Cell Lymphoma : Follicular Lymphoma
             Previous Treatments :
             Patient must have received treatment with chemotherapy and CD20 antibody previously
             Patients must have received at least two lines of therapy previously and be eligible
             to receive Rituximab Sub-Type of CD20+ B Cell Lymphoma : Nodal Marginal Zone Lymphoma
             or Splenic Marginal Zone Lymphoma
             Previous Treatments:
             Patient must have received treatment with chemotherapy and CD20 antibody previously
             Patient must have received BTK inhibitors and PI3K inhibitors, unless not available
             locally to the patient Patient must have received at least two lines of therapy
             previously and be eligible to receive Rituximab Sub-Type of CD20+ B Cell Lymphoma:
             Extra nodal Marginal Zone Lymphoma of MALT tissue
             Previous Treatments:
             Patient must have received treatment with accepted antibiotic therapy for H. Pylori as
             well as chemotherapy and CD20 antibody previously Patient must have received BTK
             inhibitors and PI3K inhibitors, unless not available locally to the patient Patient
             must have received at least two lines of therapy previously Sub-Type of CD20+ B Cell
             Lymphoma: Diffuse Large B Cell Lymphoma or Histologically transformed indolent
             lymphomas to DLBCL or High-grade B cell lymphomas
             Previous Treatments:
             Patient must have received treatment with R-CHOP / R-CVP (if not eligible for
             doxorubicin) Patient must have received High Dose Chemotherapy with Autologous Stem
             Cell Transplant, unless patient is not eligible or has refused transplant previously
             Patient must have received at least two lines of therapy previously Sub-Type of CD20+
             B Cell Lymphoma: Mantle Cell Lymphoma
             Previous Treatments:
             Patient must have received treatment with chemotherapy and CD20 antibody previously
             Patient must have received BTK inhibitors unless not available locally to the patient
             Patient must have received High Dose Chemotherapy with Autologous Stem Cell
             Transplant, unless patient is not eligible or has refused transplant previously
             Patient must have received at least two lines of therapy previously
          4. Eastern Cooperative Oncology Group (ECOG) (Appendix D) Performance status of 0 or 1
             (Patients with disease related ECOG 2 are allowed, in addition to ECOG 0 and 1).
          5. Acceptable bone marrow as described below:
             Part 1 ANC greater than1500/μL (without WBC growth factor support). Platelet count
             greater than100,000/μL without transfusion support. Hemoglobin greater than 9 g/dL
             (Transfusion is allowed to achieve this Hb). Part 2A and 2B WBC Less than 20,000/μL
             (Hydroxyurea can be given to reduce WBC count to Less than 20,000/μl). Platelet count
             greater than 50,000/μL without transfusion support. Hemoglobin greater than 9 g/dL
             (Transfusion is allowed to achieve this Hb). Part 3A and 3BANCgreater than 1000 / μL.
             Platelet count greater than 50,000/μL without transfusion support. Hemoglobin greater
             than9 g/dL (Transfusion is allowed to achieve this Hb).
          6. Acceptable organ function as described below:
             Total Bilirubin less than 1.5 x ULN; (Patients with known Gilbert's syndrome are
             allowed with a Total Bilirubin Less than 2.5 x ULN). AST (SGOT) Less Than 3 x ULN
             (Less than 5 × ULN if known liver metastases). ALT (SGPT) Less than 3 x ULN (less than
             5 × ULN if known liver metastases). Creatinine clearance (CrCl) greater than 60 mL/min
             (either measured or estimated by the Cockcroft-Gault formula). (Cockcroft-Gault
             formula for estimated creatinine clearance [eCrCl]: eCrCl = [140 - Age] × Weight [kg]
             × [0.85 if Female] / [72 × serum creatinine (mg/dL)]). Albumin greater than 3.0 g/dL
          7. Ability to swallow and retain oral medications.
          8. Negative serum pregnancy test in women of childbearing potential (WOCBP).
          9. Women of childbearing potential and men who partner with such a woman of childbearing
             potential must agree to use one or more of highly effective method(s) for
             contraception for the duration of the study, i.e.,through 28-day follow up visit,
             after discontinuation of study drug(s).
         10. Evidence of measurable disease per RECIST, v1.1 for solid tumors (Eisenhauer et al.
             2009, Appendix E) and per Lugano Criteria for Lymphoma (Cheson et al. 2014, Appendix
             J). Measurable disease for solid tumors is defined as at least one lesion that can be
             accurately measured in at least 1 dimension with a minimum size of 10 mm for non-nodal
             lesions or 15 mm in short axis for nodal lesions. For malignant lymphomas, measurable
             disease is defined as a lesion that can be accurately measured with a minimum size of
             10 mm in both dimensions or 15 mm in greatest transverse diameter. AML/MDS patients
             are per WHO 2016 criterion.
        Exclusion Criteria:
          1. Systemic anti-cancer therapy, such as chemotherapy, or biological therapy,
             immunomodulatory drug therapy, received within the past 28 days or 5 half-lives,
             whichever is shorter, from the Cycle 1 Day 1 of the study. Concomitant use of
             prednisone or medroxyprogesterone is allowed. In Part 1, Patients with CRPC (castrate
             resistant prostate cancer) should continue to receive ongoing medical castration with
             LHRH analogues, and such patients are allowed.
          2. Acute promyelocytic leukemia (AML M3 subtype).
          3. Patients eligible for intensive chemotherapy for AML (such as the 3 + 7 regimen).
          4. CML in blast crisis (i.e., patients with known bcr-abl positive disease).
          5. Presence of an acute or chronic toxicity resulting from prior anti cancer treatment,
             with the exception of alopecia or nail changes, that has not resolved to Grade Less
             than 1, as determined by NCI CTCAE v 5.0 (Appendix G).
          6. Definitive Radiotherapy within the last 21 days of Cycle 1 Day 1 (limited field
             palliative radiation is allowed and no restrictions during the screening period or
             during the trial).
          7. Use of any investigational agent within 28 days or 5 half-lives (whichever is shorter)
             prior to Cycle 1 Day 1.
          8. Known symptomatic or untreated or recently treated (Less than 6 months of screening)
             central nervous system (CNS) metastases or CNS lymphoma or CNS leukemia. Patients with
             previously treated (greater than 6 months of screening) CNS metastases or CNS lymphoma
             or CNS leukemia and are now stable and asymptomatic, from CNS perspective, are
             allowed.
          9. Major surgery Less than 28 days from Cycle 1 Day 1 (major surgery is defined as a
             procedure requiring general anesthesia).
         10. Known to be human immunodeficiency virus (HIV) positive or have an acquired
             immunodeficiency syndrome-related illness.
         11. Known active or chronic hepatitis B or hepatitis C infection.
         12. Uncontrolled congestive heart failure (New York Heart Association [NYHA] Class 2-4),
             angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery
             bypass graft surgery, or transient ischemic attack, or pulmonary embolism within 3
             months prior to Cycle 1 Day 1
         13. Ongoing cardiac dysrhythmias requiring treatment of any gradeor treatment of cardiac
             dysrhythmias in past 3 months, before Cycle 1 Day 1.
         14. The QTcF (corrected QT interval Fridericia method) value in the screening ECG greater
             than 450 ms in males and greater than 460 ms in females.
         15. Previous allogeneic stem cell or bone marrow transplantation
         16. NHL subtypes of Burkitt Lymphoma, Lymphoblastic Lymphoma, AIDS related lymphoma,
             Primary CNS Lymphoma, Waldenstrom Macroglobulinemia, Castleman Disease, Post
             Transplant Lymphoproliferative Disorder and anaplastic large B cell lymphoma.
         17. Previous or concomitant additional malignancy, except for basal-cell or squamous cell
             carcinoma of the skin or carcinoma in-situ of the uterine cervix; patients with other
             malignancies are eligible if they have remained disease free for at least 2 years
             prior to trial entry and in the opinion of the investigator deemed to have a low
             likelihood of recurrence.
         18. Pregnant or lactating women.
         19. Any clinically significant medical, psychiatric or social condition; or laboratory
             abnormality that may increase the risk of trial participation or may interfere with
             the informed consent process and/or with compliance with the requirements of the trial
             or may interfere with the interpretation of the trial results and, in the
             Investigator's opinion, would make the patient inappropriate for entry into this
             trial.