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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Abraxane


Participation Criteria
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Eligibility Criteria
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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)

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1: Dose escalation as a single agent (all tumor types); Dose escalation in combination with Abraxane (Breast Cancer); Phase 2: Dose expansion as a single agent or in combination with Abraxane (breast cancer)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation<br>Advanced solid tumors or metastatic breast cancer: Treatment with a single oral agent, ORIN1001. Relapsed, refractory metastatic breast cancer: Treatment with a combination of ORIN1001 and Abraxane. | Drug: Abraxane<br>* The doses of ORIN1001 in both dose escalation and dose expansion will be 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600mg, 800 mg, 1,000 mg, 1,200 mg Weekly paclitaxel will be 80 mg/m2 given intravenously for the dose escalation and dose expansion phases. cohorts as follows: 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1,000 mg, 1,300 mg and 1,500 mg administered for 21 days (one cycle).<br>* Other names: ORIN1001;|
| Experimental: Phase 2: Dose Expansion<br>Relapsed refractory metastatic breast cancer that are Triple negative, ER+ or HER2- and treated with a single agent (ORIN1001) or in combination with ORIN1001 and Abraxane. | Drug: Abraxane<br>* The doses of ORIN1001 in both dose escalation and dose expansion will be 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600mg, 800 mg, 1,000 mg, 1,200 mg Weekly paclitaxel will be 80 mg/m2 given intravenously for the dose escalation and dose expansion phases. cohorts as follows: 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1,000 mg, 1,300 mg and 1,500 mg administered for 21 days (one cycle).<br>* Other names: ORIN1001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of MTD/RP2D of single-agent daily ORIN1001 when administered orally in subjects with advanced solid tumors: NCI CTCAEv5 Common Toxicity Criteria | To determine the safety of the maximal tolerated dose/ recommended Phase 2 dose (MTD/RP2D). Incidence of the safety population will consist of all subjects who received a dose of study drug. Treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. Adverse events will be evaluated and recorded according to NCI CTCAEv5 Common Toxicity Criteria and will use medical terminology based on the Medical Dictionary for Regulatory Activities Terminology (MedDRA). | From first dose up to 21 days after last dose | 
| To determine the safety MTD/RP2D of daily ORIN1001 when administered orally in combination with paclitaxel given intravenously at 175 mg/m2 once every three weeks in subjects with relapsed refractory metastatic breast cancer | Incidence of the safety population will consist of all subjects who received a dose of study drug. Treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. Adverse events will be evaluated and recorded according to NCI CTCAEv5 Common Toxicity Criteria and will use medical terminology based on the Medical Dictionary for Regulatory Activities Terminology (MedDRA). | From first dose up to 21 days after last dose | 
| To evaluate the safety and tolerability of single-agent daily ORIN1001 when administered orally in the dose escalation and expansion stages of the study: NCI CTCAEv5 Common Toxicity Criteria | Incidence of the safety population will consist of all subjects who received a dose of study drug. Treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. Adverse events will be evaluated and recorded according to NCI CTCAEv5 Common Toxicity Criteria and will use medical terminology based on the Medical Dictionary for Regulatory Activities Terminology (MedDRA). | From first dose up to 21 days after last dose | 
| To evaluate the safety and tolerability of daily ORIN1001 when administered orally in combination with Abraxane given intravenously at 100 mg/m2 once weekly for 3 weeks in the dose escalation and expansion stages of the study | Incidence of number of participants with clinically significant change in vital signs. Vital signs include body weight, body temperature, resting blood pressure, pulse and respiratory rate. | From first dose up to 28 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the peak concentrations (Cmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent peak concentrations (Cmax) of ORIN1001 by direct inspection of the plasma concentration-time curves of ORIN1001 following single and repeat oral doses of ORIN 1001 as a single agent and in combination with Abraxane. | 2 months | 
| To evaluate the time to peak concentrations (Tmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent time to peak concentrations (Tmax) of ORIN1001 by direct inspection of the plasma concentration-time curves of ORIN1001 following single and repeat oral doses of ORIN 1001 as a single agent and in combination with Abraxane. | 2 months | 
| To evaluate the area under the plasma concentration versus time curve (AUC) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent area under the plasma concentration versus time curve (AUC) for ORIN1001 following single doses of ORIN 1001 as a single agent and in combination with Abraxane. | 2 months | 
| To evaluate the last time point with a quantifiable concentration (AUClast) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent plasma levels of ORIN1001 from the time of dosing to the last time point with a quantifiable concentration (AUClast) of ORIN1001 following single doses of ORIN 1001 as a single agent and in combination with Abraxane. | 2 months | 
| To evaluate the plasma concentration end of a dosing interval (Ctau) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent plasma concentrations (Cmax) of ORIN1001 as single agent or in combination with Abraxane at the end of a dosing interval (Ctau), where tau is 24 hours for once daily dosing. | 2 months | 
| To evaluate the average plasma concentration (Cav) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the average plasma concentration (Cav) of ORIN1001 as single agent or in combination with Abraxane during the dosing interval. | 2 months | 
| To evaluate the minimum plasma concentrations (Cmin) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the the minimum plasma concentrations (Cmin) reached by ORIN1001 as single agent or in combination with Abraxane prior to administration of a second dose. | 2 months | 
| To evaluate the elimination constant (λz) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent plasma elimination constant (λz) for ORIN1001 as a single agent or in combination with Abraxane. | 2 months | 
| To evaluate the terminal half-life (T1/2) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent terminal plasma half-life of ORIN1001 (T1/2) as a single agent or in combination with Abraxane. | 2 months | 
| To evaluate the plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the dose-dependent apparent total plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent or in combination with Abraxane. | 2 months | 
| To evaluate the volume of distribution (Vz/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane. | Determine the apparent volume of distribution (Vz/f) during terminal phase after oral administration of ORIN1001 as a single agent or in combination with Abraxane. | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors, Breast Cancer