AUR103 Calcium in Advanced Neuroendocrine Tumours (BHARAT-3 Study)

A Phase 2 Study Evaluating the Efficacy and Safety Agent AUR103 Calcium in Patients With Advanced, Well or Moderately Differentiated Neuroendocrine Tumours (BHARAT-3)

A phase 2 Study Evaluating the Efficacy and Safety of Single Agent AUR103 Calcium in Patients with Advanced, Well or Moderately differentiated Neuroendocrine Tumours.

This is a Proof of Concept (PoC) Phase 2 study of AUR103 calcium in patients with advanced, well or moderately differentiated neuroendocrine tumours.

The main objective is to evaluate the efficacy of AUR103 calcium in patients with well or moderately differentiated neuroendocrine tumors.

Patients with relapsed/refractory well or moderately differentiated neuroendocrine tumors.

AUR103 calcium will be administered twice daily. Patients will receive AUR103 calcium until disease progression or intolerable toxicity.

Inclusion Criteria:

1. Age ≥ 18 years.

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

3. Pathologically confirmed, well or moderately differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumour.

4. Patients should have progressed after at least one line of therapy.

   Notes:

   1. All previous treatments are allowed
   2. There is no upper limit on the number of prior lines of therapy.
   3. Patient should have received at least one FDA approved therapy for his/her disease (i.e., Patient should have received at least one of everolimus, sunitinib, cabozantinib or Lu177 dotatate for his/her specific NET, as per FDA approved package insert).
   4. SSA (Somatostatin Analogues) alone is not considered a line of therapy for Inclusion criterion 4.

5. Disease progression with last line of therapy.

6. Measurable disease by RECISTv1.1.

7. If the patient is receiving Somatostatin analouges (SSA), the patient should be on stable doses for at least 2 months.

   [Note: Concomitant Somatostatin analouges (SSA) are allowed. No other therapies for NET are allowed along with study drug (e,g., everolimus, sunitinib, cabozantinib, peptide receptor radionuclide therapy (PRRT), chemotherapy etc.)].

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

   1. ANC ≥1000/ μL
   2. Platelet count ≥ 80,000/μL
   3. Hemoglobin ≥ 9 g/dL (Transfusion is allowed to achieve this Hb)

9. Total Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert's syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN).

10. AST (SGOT) ≤ 3 x ULN (≤ 5 x ULN if known liver metastasis).

11. ALT (SGPT) ≤ 3 x ULN (≤ 5 x ULN if known liver metastasis).

12. Creatinine clearance (CrCl) ≥ 60 mL/min (either measured or estimated by the Cockcroft-Gault formula).

(Note: Cockcroft-Gault formula for estimated creatinine clearance [eCrCl]: eCrCl = [140- Age] × Weight [kg] × [0.85 if Female] / [72 × serum creatinine (mg/dL)]).

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Exclusion Criteria:

1. Neuroendocrine carcinoma, such as small cell carcinoma.

2. Grade 3 neuroendocrine tumours (NET) and/or Poorly differentiated NET.

3. Patients with known MEN-1 (Multiple Endocrine Neoplasia-1) or MEN-2 (Multiple Endocrine Neoplasia-2) syndromes.

4. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral AUR103 calcium.

5. Systemic anti-cancer therapy, such as small molecule TKIs, mTOR inhibitors, 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 SSA is allowed].

6. Patients who have used PRRT as a previous line would require 6 weeks from the last dose, before Cycle 1 Day 1.

7. Presence of an acute or chronic toxicity resulting from prior anticancer treatment, except for alopecia or nail changes, that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 5.0.

8. Use of any investigational agent within 21 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.

9. Known symptomatic or untreated or recently treated (≤ 6 months of screening) CNS metastases. Patients with previously treated (> 6 months of screening) brain metastasis and are now stable and asymptomatic, from CNS perspective, are allowed.

10. Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia).

11. Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization.

12. Presence of any additional malignancy within last 3 years, except basal-cell or squamous cell carcinoma of the skin or carcinoma-in situ of the uterine cervix.

    [Note: 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].

13. Active infection requring 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].

14. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness.

15. Known active or chronic hepatitis B (HBsAg +ve), hepatitis C infection (HCV antibody +ve).

16. Expected to require any other form of antineoplastic therapy or targeted therapy while on study.

17. 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.

18. Ongoing cardiac dysrhythmias requiring treatment of any grade or treatment of cardiac dysrhythmias in past 3 months, before Cycle 1 Day 1.

19. Mean QTcF (Fridericia) interval >460 ms on ECG at screening or at Cycle 1 Day 1 pre-dose.

20. 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 principal investigator (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.

21. Current swab-positive or suspected (under investigation) COVID-19 infection or fever and other signs or symptoms suggestive of COVID19 infection with recent contact of person(s) with confirmed COVID19 infection, at screening or Day 1 of Cycle 1.

22. Positive pregnancy test for women of child-bearing potential (WOCBP) at the screening or enrolment visit, or lactating women.

23. Women of child-bearing potential (WOCBP) 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).

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