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

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:

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

Inclusion criteria

for Dose Escalation and Dose Expansion

• Adults aged ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Life expectancy of 3-4 months
• Have at least one measurable lesion per RECIST 1.1
• Have adequate organ function, including all of the following:

• 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
• Hepatic: total bilirubin ≤2 x ULN, transaminases (AST/SGOT and/or ALT/SGPT) ≤ 3X ULN;alkaline phosphatase ≤ 5 x ULN
• Renal: 24-hour creatinine clearance ≥ 30 mL/min calculated
• Adequate tissue sample from either archival tumor tissue or fresh biopsy of tumor at the screening for tumor genotyping.
• 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.
• 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.
• Ability to understand and willingness to sign an informed consent prior to any study specific procedures.
• Resolution of all toxicities (except alopecia) from prior therapy to ≤ Grade 1 (CTCAE v5)

Exclusion criteria

• Does not meet inclusion criteria
• 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

• Greater than Class II heart failure using New York Heart Association (NYHA) criteria
• The subject has uncontrolled human immunodeficiency virus (HIV) infection or active hepatitis B or C infection or other known active and/or uncontrolled infection
• Active autoimmune disease that is not appropriately controlled with treatment
• Active malignancy with the exception of:

• adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
• adequately treated stage I cancer from which the subject is currently in remission, or
• any other cancer from which the subject has been disease-free for ≥3 years;
• Any serious uncontrolled medical or psychological disorder that would impair the ability to receive protocol therapy
• Any condition which places the subject at unacceptable risk or confounds the ability of the investigator to interpret study data
• The subject is pregnant or lactating woman. Any woman who becomes pregnant during the study will be withdrawn from the study.
• 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.
• 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)
• Greater than Grade 1 neuropathy (combination arm only)