ORIN1001 in Patients with Advanced Solid Tumors and Relapsed Refractory Metastatic Breast Cancer

A Phase 1/2, Open Label, Dose-Escalation and Expansion Study of Oral ORIN1001 with and Without Chemotherapy in the Treatment of Subjects with Solid Tumors

This study evaluates the anti-tumor effects of ORIN 1001 in patients with advanced solid tumors or relapsed refractory metastatic breast cancer (patients with progressive disease after receiving at least two lines of therapy in the advanced setting).

This is a first in human, Phase 1/2, open label, dose escalation and dose expansion study that consists of two stages:

Phase 1: A dose escalation stage to determine the MTD/RP2D of ORIN1001 when given as a single agent in up to 30 subjects with advanced solid tumors. In addition, a dose escalation stage to determine the MTD/RP2D of daily ORIN1001 in combination with Abraxane given intravenously in up to 18 subjects with relapsed refractory metastatic breast cancer (TNBC or ER+ HER2-).

Phase 2: An expansion stage of ORIN1001 alone (Cohort A: TNBC) and in combination with Abraxane (Cohort B: Myc+; Cohort C: ER+ HER2-, and Cohort D: TNBC) to estimate efficacy in up to 120 subjects with relapsed refractory metastatic breast cancer.

Inclusion Criteria:

For dose escalation with ORIN1001 alone:

-Male or female with advanced solid tumors for which no effective standard of care treatments are available

For dose escalation with ORIN1001 in combination with Abraxane:

-Males or females with relapsed refractory metastatic breast cancer (TNBC or ER+, HER2-) must have progressed through at least 2 lines of therapy and for whom there are no available therapies that confer a clinical benefit

For dose expansion:

a. Males or females with relapsed refractory metastatic breast cancer including:

1. TNBC (i.e. estrogen receptor (ER)-, progesterone receptor-, and human epidermal growth factor receptor 2 [HER2]-)
2. ER+ HER2- breast cancer

Inclusion Criteria for Dose Escalation and Dose Expansion

1. Adults aged ≥ 18 years

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

3. Life expectancy of 3-4 months

4. Have at least one measurable lesion per RECIST 1.1

5. Have adequate organ function, including all of the following:

   1. Adequate bone marrow reserve as defined by: ANC≥1.0 x 10 9/L; platelet count ≥75 x 10 9/L; hemoglobin ≥9 g/dL
   2. Hepatic: total bilirubin ≤2 x ULN, transaminases (AST/SGOT and/or ALT/SGPT) ≤ 3X ULN;alkaline phosphatase ≤ 5 x ULN
   3. Renal: 24-hour creatinine clearance ≥ 30 mL/min calculated

6. Adequate tissue sample from either archival tumor tissue or fresh biopsy of tumor at the screening for tumor genotyping.

7. Male subjects must be surgically sterile or must agree to use physician approved contraception for 7 days prior to the first study drug administration to 30 days after the last dose of study treatment.

8. Women of childbearing potential must have negative serum pregnancy test within 14 days prior the first administration of study drug and agree to use physician-approved contraception from 30 days prior to the first study drug administration to 30 days following the last study drug administration.

9. Ability to understand and willingness to sign an informed consent prior to any study specific procedures.

10. Resolution of all toxicities (except alopecia) from prior therapy to ≤ Grade 1 (CTCAE v5)

Exclusion Criteria:

1. Does not meet inclusion criteria

2. Received any of the following within the specified time frame prior to the first administration of study drug:

   i. Excluding those with a history of coagulopathy ii. Excluding those who require concurrent use of anti-coagulants or anti-platelet medication, with exception of aspirin doses ≤ 81 mg/day, prophylaxis subcutaneous (SC) heparin or SC low-molecular weight heparin for deep vein thrombosis (DVT) prophylaxis or heparin flushes to maintain IV catherer patency iii. Excluding subjects that have Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) >1.5 x ULN b.Prior chemotherapy or other systemic anticancer therapy within 3 weeks or 5 times the plasma half-life of the drug, whichever is shorter; c.Prior radiotherapy within 2 weeks; d.Major surgery within 2 weeks; e.Prior treatment with investigational drugs within 4 weeks; f. Myocardial infarction, uncontrolled angina,severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the fist dose of study drug

3. Greater than Class II heart failure using New York Heart Association (NYHA) criteria

4. The subject has uncontrolled human immunodeficiency virus (HIV) infection or active hepatitis B or C infection or other known active and/or uncontrolled infection

5. Active autoimmune disease that is not appropriately controlled with treatment

6. Active malignancy with the exception of:

   1. adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
   2. adequately treated stage I cancer from which the subject is currently in remission, or
   3. any other cancer from which the subject has been disease-free for ≥3 years;

7. Any serious uncontrolled medical or psychological disorder that would impair the ability to receive protocol therapy

8. Any condition which places the subject at unacceptable risk or confounds the ability of the investigator to interpret study data

9. The subject is pregnant or lactating woman. Any woman who becomes pregnant during the study will be withdrawn from the study.

10. Known active uncontrolled or symptomatic brain metastases. Patients with a history of such metastases that have been treated and are stable ≥28 days may be enrolled. Patients with no steroid use for at least 2 weeks prior to the time of enrollment are permitted.

11. Failed to respond to the most recent dose of Abraxane and must have been received at least 12 months prior to starting treatment.(combination arm only)

12. Greater than Grade 1 neuropathy (combination arm only)