Study Evaluating Safety Pharmacokinetics and Pharmacodynamics of AUR112 in Patients With Relapsed Advanced Lymphoma

A Phase 1, Open Label, Dose Escalation, Multicenter, First-in-Human (FIH) Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of Oral AUR112 In Patients With Relapsed Advanced Lymphoma (ADITI-1)

A Phase 1, Open Label, Dose Escalation, Multicenter, First-in-Human (FIH) Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of Oral AUR112 in Patients with Relapsed Advanced Lymphoma (ADITI-1)

The main objective of Part 1 will be to evaluate the safety and tolerability of the study drug AUR112.

Dose escalation of single agent AUR112 will be conducted in the classic 3+3 design. Safety including Dose Limiting Toxicities (DLTs), PK, and PD will be assessed at each dose. Dose escalation will continue until safety limits are reached or the escalation will stop earlier if PK/PD data suggest that a biologically active dose has reached.

The objective is to determine dose(s) which will be investigated in future trials.

Inclusion Criteria:

1. Males and females ≥ 18 years of age

2. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1

3. Acceptable bone marrow and organ function at screening as described below:

   1. ANC ≥ 1000/μL (without WBC growth factor support)
   2. Platelet count: For patients with CLL ≥ 50,000/μL; For patients with lymphomas ≥ 75,000/μL without bone marrow involvement and ≥ 50,000/μL with bone marrow involvement. These thresholds should be qualified without platelet transfusion support.
   3. Hemoglobin ≥ 9 g/dL (RBC Transfusion is allowed to achieve this Hb)
   4. Total Bilirubin ≤ 1.5 x ULN; (Patients with known Gilbert's syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN)
   5. AST (SGOT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases)
   6. ALT (SGPT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases)
   7. Creatinine clearance (CrCl) ≥ 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)]).

4. Ability to swallow and retain oral medications

5. Histopathological diagnosis of Non-Hodgkin Lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL) or Hodgkin disease. Note:

5a. The lymphoma should be either in Stage III or IV according to Lugano classification (Cheson et al. 2014) at screening. 5b. The lymphomas included in this study must fall within one of the following 2017 World Health Organization categories except lymphoma mentioned in Exclusion criterion #5:

• Mature B-cell neoplasms (excluding plasma cell neoplasms, heavy chain disease, and primary central nervous system [CNS] lymphoma).

• Mature T- and NK-cell neoplasms.

• Hodgkin lymphomas 5c. The CLL should be Binet Stage C/Rai stage III or IV, as per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (Hallek et al. 2018).

  6. In the case of subjects who have lymphoma for which high-dose chemotherapy and autologous stem cell transplantation (HDASCT) is considered a standard curative therapy, eligibility for this study requires that the subject's disease has relapsed after HDASCT, or the subject is not eligible for HD-ASCT, or that the subject has refused HD-ASCT.

  7. In the case of patients who have lymphoid malignancies for which CAR-T therapy is indicated, eligibility for this study requires that the disease has relapsed after CAR-T, or the patient is not eligible for CAR-T, or the patient has refused CAR-T, or the CAR-T is not available locally.

  8. Evidence of measurable disease as per Lugano Criteria for Lymphoma (Cheson et al. 2014) or evidence of measurable disease as per iwCLL Criteria for CLL (Hallek et al. 2018). Note: Patients with Small Lymphocytic Lymphoma (SLL) alone or in combination with CLL are allowed.

  9. Standard curative measures do not exist, and the patient must have exhausted all effective therapies available locally. The patients must have relapsed or refractory to at least 2 prior lines of systemic therapies for NHL or CLL, or Hodgkin disease.

Note:

• Any cancer patient with access to any effective therapy locally must not be enrolled.
• Patients with CLL should have documented evidence for progressive or symptomatic disease (active disease) and must have indications for treatment (Hallek et al 2018).
• Patients with indolent lymphomas also must have indications for treatment, such as the GELF (Brice et al 1997) or BNLI criterion (Ardeshna et al 2003)

Exclusion Criteria:

1. Systemic anti-cancer therapy, such as chemotherapy, biological therapy, or immunomodulatory drug therapy received within the past 28 days or 5 half-lives, whichever is longer, from the Cycle 1 Day 1 of the study. Note: Concomitant use of low dose prednisone (up to 10 mg/day) is allowed
2. Presence of an acute or chronic toxicity resulting from prior anticancer treatment, with the exception of alopecia or nail changes, that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 5.0. 1
3. 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).
4. Use of any investigational agent within 28 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1
5. Patients with Burkitt's lymphoma, Burkitt-like lymphoma, posttransplant lymphoproliferative disease, primary mediastinal large-B cell lymphoma, cutaneous lymphomas, mycosis fungoides (MF), or Sezary syndrome (SS).
6. Known symptomatic or untreated or recently treated (≤ 6 months of screening) central nervous system (CNS) lymphoma. Patients with previously treated (> 6 months of screening) CNS lymphoma and are now stable and asymptomatic, from CNS perspective, are allowed.
7. Patients with lymphoma that requires immediate cytoreductive therapy.
8. Patients with low-grade lymphoma or indolent lymphoma that does not meet conventional criteria (Jeong SH, 2022) for requiring treatment.
9. Patients on drugs which are inhibitors of P-gp or BCRP or UGT1A1 and when these drugs cannot be discontinued from at least one week prior to Cycle 1 Day 1. Note: These drugs will be prohibited during Cycle 1 of therapy.
10. Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia)
11. Active infection requiring systemic therapy. Note: Prophylactic use of antibiotics is allowed. Any infection detected during screening period which is resolved adequately according to investigator before the Cycle 1 Day 1, is allowed.
12. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness.
13. Known active or chronic hepatitis B (HBsAg +ve) or hepatitis C infection (HCV antibody +ve).
14. The patient who is expected to require any other form of antineoplastic therapy or targeted therapy while on study
15. . 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.
16. Ongoing cardiac dysrhythmias requiring treatment of any grade or treatment of cardiac dysrhythmias in past 3 months, before Cycle 1 Day 1.
17. QTcF (Fridericia) interval >470 ms on ECG at screening and/or at Cycle 1 Day 1 pre-dose.
18. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or significant gastritis, active bleeding diatheses, presence of any major medical illness (e.g. renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or psychiatric illness/social situations or clinically significant laboratory / ECG abnormalities at screening, any or a combination of illnesses, which, in the opinion of the PI, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study.
19. Current swab-positive or suspected (under investigation) Covid19 infection or fever and other signs or symptoms suggestive of Covid-19 infection with recent contact of person(s) with confirmed Covid-19 infection, at screening or Cycle 1 Day 1.
20. History of another primary malignancy within 5 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study.
21. Positive pregnancy test for women of child-bearing potential (WOCBP) at the screening or enrolment visit.
22. Lactating women or WOCBP or a man with a partner who has childbearing potential, who are neither surgically sterilized nor willing to use reliable contraceptive methods(hormonal contraceptive, IUD, or any double combination of male or female condom, spermicidal gel, diaphragm, sponge, cervical cap) during the screening period, while on AUR112 and at least 28 days after last dose