A Study Evaluating the Safety and Efficacy of AUR107 in Patients With Relapsed Advanced Malignancies (SHAKTI-1)

Study Overview
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Brief Summary
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An open-label, first-in-human, Phase 1 study in adult patients with relapsed advanced malignancies will be done to assess AUR107 safety, tolerability, pharmacokinetics, pharmacodynamics, and optimal biological dose.

Detailed Description
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This is a Phase I, Open Label, Dose-Escalation, First-in-Human study in adult patients with select relapsed advanced malignancies. The safety and tolerability of oral AUR107 will be evaluated in patients with selected advanced solid tumors (Non-small cell lung cancer, Gastric cancer, Urothelial cancer, Kidney cancer, Colon cancer, and Esophageal cancer) who do not have any available curative or life-prolonging treatment options and have exhausted all effective locally available therapies. The traditional 3+3 design for dose escalation will be used to evaluate the safety, pharmacokinetics/pharmacodynamics, and determine the Optimal Biological Dose of AUR107 as a single agent. The Optimal Biological Dose will be selected using a totality of safety, PK, and PD data.

Official Title
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A Phase 1, Open Label, Dose Escalation, Dose Expansion, Multicenter, First in Human Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Oral AUR107 in Patients With Relapsed Advanced Malignancies (SHAKTI-1)

Conditions
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Relapsed Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: AUR107


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1. Acceptable bone marrow and organ function at screening as described below: ANC ≥ 1500/μL (without WBC growth factor support) Platelet count ≥ 100,000/μL without transfusion support Hemoglobin ≥ 9 g/dL (Transfusion is allowed to achieve this Hb) Total Bilirubin ≤ 1.5 x ULN; (Patients with known Gilbert's syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN) AST (SGOT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases) ALT (SGPT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases) Creatinine clearance (CrCl) ≥ 60 mL/min (either measured or estimated by the Cockcroft-Gault formula). Ability to swallow and retain oral medications. Histopathological diagnosis of a solid tumor. Note: The solid tumors must be in Stage IV at screening. Evidence of measurable disease per RECIST, v1.1 for solid tumors. Standard curative measures do not exist, and the patient must have exhausted all effective therapies available locally. Notes: 7a. At a minimum, solid tumor patients must have received at least two lines of systemic therapies in the metastatic incurable settings (these two lines must be in the metastatic setting and not in the earlier stage of cancer). 7b. Any cancer patient with access to any effective therapy must not be enrolled Exclusion Criteria: 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 Cycle 1 Day 1 of the study. Note: Concomitant use of low-dose prednisone (up to 10 mg/day) or medroxyprogesterone is allowed. Note: Patients with CRPC (castrate-resistant prostate cancer) should continue to receive ongoing medical castration with LHRH analogs, and such patients are allowed. Presence of 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. 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) • Use of any investigational agent within 28 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. Use of drugs which are moderate / strong CYP3A4 inducers and/or drugs which are predominantly metabolized by CYP3A4 within 1week or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. • Note: This class of drugs are also prohibited during DLT evaluation period and must be either avoided or used with caution beyond DLT evaluation period. Known symptomatic or untreated or recently treated (≤ 6 months of screening) central nervous system (CNS) metastases. Patients with previously treated (> 6 months of screening) CNS metastases and are now stable and asymptomatic, from CNS perspective, are allowed. Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia). Patients with leukemia, myelodysplastic syndrome, multiple myeloma, or lymphoma. Active infection requiring systemic therapy. Note: Prophylactic use of antibiotics is allowed. Any infection detected during the screening period which is resolved adequately according to investigator before the Cycle 1 Day 1, is allowed. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. Known active or chronic hepatitis B (HBsAg +ve) or hepatitis C infection (HCV antibody +ve). The patient who is expected to require any other form of antineoplastic therapy or targeted therapy while on study. 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. Ongoing cardiac dysrhythmias requiring treatment of any grade or treatment of cardiac dysrhythmias in the past 3 months, before Cycle 1 Day 1. QTc (Bazzett) interval >460 ms on ECG at screening and/or at Cycle 1 Day 1 pre-dose. 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. Current swab-positive or suspected (under investigation) Covid-19 infection or fever and other signs or symptoms suggestive of Covid-19 infection with recent contact of the person(s) with confirmed Covid-19 infection, at screening or Day 1 of Cycle 1. Positive pregnancy test for women of childbearing potential (WOCBP) at the screening or enrolment visit. Lactating women or WOCBP who are neither surgically sterilized nor willing to use reliable contraceptive methods. (hormonal contraceptive, IUD, or any double combination of the male or female condom, spermicidal gel, diaphragm, sponge, cervical cap).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation 3+3 Design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AUR107, 5mg to 200mg<br>Currently, planned dose levels are 5 mg QD, 10 mg QD, 20 mg QD, 40 mg QD, 60 mg QD, 90 mg QD, 135 mg QD, and 200 mg QD | Drug: AUR107<br>* Once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First cycle Dose Limiting Toxicities (DLT) | Assess dose limiliting toxicities of AUR107 | 28 days | 
| Safety of AUR107 as measured by the number of participants with treatment-related adverse events (AE) graded according to NCI CTCAE version 5.0 | The assessment of safety was based on the frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study drug, and abnormalities in specific clinical laboratory assessments. AEs and laboratory values will be graded for severity according to the NCI CTCAE version 5.0. | 28 days | 
| Optimal Biological Dose | Determine optimal Biological dose | 28 days | 
| Pharmacokinetics: Maximum concentration (Cmax) | Maximum concentration of AUR107 | Day 1 and Day 15 | 
| Pharmacokinetics: Time to Maximum concentration (Tmax) | Tmax in hours | Day 1 and Day 15 | 
| Pharmacokinetics: Area under the curve (AUC) | Area under the curve (AUC) of AUR 107 in h* mcg/mL | Day 1 and Day 15 | 
| Pharmacokinetics: Mean Residence Time (MRT) | Average time the drugs stays in the body | Day 1 and Day 15 | 
| Pharmacokinetics: Terminal elimination half-life | Terminal elimination half-life of AUR 107 in hours | Day 1 and Day 15 | 
| Maximum concentration (Cmax) administered under fasting/fed condition | Compare in fast and fed conditions | Day 8 and Day 9 | 
| Time to Maximum concentration (Tmax) administered under fasting/fed condition | Compare Tmax in fast and fed conditions | Day 8 and Day 9 | 
| Area under curve (AUC) administered under fasting/fed condition | Compare AUC in fast and fed conditions | Day 8 and Day 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapse malignant neoplasm, Non small cell lung cancer, Gastric cancer, Colon cancer, Esophageal cancer, Kidney cancer