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

Phase 1

Completed

• Conditions: Advanced Solid Tumor; Metastatic Breast Cancer
• Interventions: Drug: ORIN1001; Drug: Abraxane

• Registration Number: NCT03950570
• Lead Sponsor: Orinove, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-04-23
• Study First Submitted QC: 2019-05-14
• Study First Posted: 2019-05-15
• Study Start: 2019-05-25
• Primary Completion: 2023-01-30
• Study Completion: 2023-01-30
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-30
• Last Update Posted: 2024-12-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 58

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1a: Dose Escalation with ORIN1001	ORIN1001	In patients with advanced solid tumors or metastatic breast cancer: Treatment with a single oral agent, ORIN1001.
Experimental Phase 1b: Dose escalation - ORIN1001 in combination with Abraxane dose	ORIN1001	In patients with Relapsed, refractory metastatic breast cancer: Treatment with a combination of ORIN1001 and Abraxane.
Experimental Phase 1b: Dose escalation - ORIN1001 in combination with Abraxane dose	Abraxane	In patients with Relapsed, refractory metastatic breast cancer: Treatment with a combination of ORIN1001 and Abraxane.

Primary Outcome Measures

Name	Time	Method
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	From first dose up to 21 days after last dose	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).
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	From first dose up to 21 days after last dose	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).
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	From first dose up to 21 days after last dose	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).
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	From first dose up to 28 days after last dose	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.

Secondary Outcome Measures

Name	Time	Method
To evaluate the peak concentrations (Cmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	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.
To evaluate the time to peak concentrations (Tmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	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.
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.	2 months	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.
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.	2 months	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.
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.	2 months	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.
To evaluate the average plasma concentration (Cav) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	Determine the average plasma concentration (Cav) of ORIN1001 as single agent or in combination with Abraxane during the dosing interval.
To evaluate the minimum plasma concentrations (Cmin) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	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.
To evaluate the elimination constant (λz) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	Determine the dose-dependent plasma elimination constant (λz) for ORIN1001 as a single agent or in combination with Abraxane.
To evaluate the terminal half-life (T1/2) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	Determine the dose-dependent terminal plasma half-life of ORIN1001 (T1/2) as a single agent or in combination with Abraxane.
To evaluate the plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	Determine the dose-dependent apparent total plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent or in combination with Abraxane.
To evaluate the volume of distribution (Vz/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.	2 months	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.

Trial Locations

Locations (20)

University of California Irvine Medical Center (UCIMC) - Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

University of California Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center (JCCC) - Oncology Center - Westwood; 🇺🇸 Westwood, California, United States

University of Colorado Anschutz Medical Campus; 🇺🇸 Denver, Colorado, United States

Highlands Ranch Hospital; 🇺🇸 Highlands Ranch, Colorado, United States

University of Colorado Lone Tree Medical Center; 🇺🇸 Lone Tree, Colorado, United States

University of Miami Hospital and Clinics - Sylvester Comprehensive Cancer Center; 🇺🇸 Miami, Florida, United States

Cancer Center of Kansas; 🇺🇸 Wichita, Kansas, United States

St Lukes Cancer Institute; 🇺🇸 Kansas, Missouri, United States

Roswell Park Comprehensive Cancer Center (RPCCC) (Roswell Park Cancer Institute (RPCI)); 🇺🇸 Buffalo, New York, United States

Northwell Health; 🇺🇸 New Hyde Park, New York, United States

Northwell Heath Cancer Institute; 🇺🇸 New Hyde Park, New York, United States

NYU Langone Health; 🇺🇸 New York, New York, United States

Gabrail Cancer Center; 🇺🇸 Canton, Ohio, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute; 🇺🇸 Nashville, Tennessee, United States

Baylor College of Medicine Medical Center; 🇺🇸 Houston, Texas, United States

Banner MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

University of Arizona Cancer Center; 🇺🇸 Tucson, Arizona, United States

UCLA Health Burbank Specialty Care; 🇺🇸 Burbank, California, United States

UCLA Health Laguna Hills Cancer Care; 🇺🇸 Laguna Hills, California, United States