Clinical trial NCT03950570: ORIN1001 in Patients with Advanced Solid Tumors and Relapsed Refractory Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Metastatic Breast Cancer
Keywords: Solid tumors, Breast Cancer
Lead sponsor: Orinove, Inc.
Sponsor class: INDUSTRY
First posted: 2019-05-15
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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
timeFrame: From first dose up to 21 days after last dose
measure: 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
timeFrame: From first dose up to 21 days after last dose
measure: 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
timeFrame: From first dose up to 21 days after last dose
measure: 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
timeFrame: From first dose up to 28 days after last dose
Secondary outcomes:
measure: To evaluate the peak concentrations (Cmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the time to peak concentrations (Tmax) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: 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.
timeFrame: 2 months
measure: 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.
timeFrame: 2 months
measure: 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.
timeFrame: 2 months
measure: To evaluate the average plasma concentration (Cav) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the minimum plasma concentrations (Cmin) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the elimination constant (λz) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the terminal half-life (T1/2) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
measure: To evaluate the volume of distribution (Vz/f) of ORIN1001 after oral administration as a single agent and in combination with Abraxane.
timeFrame: 2 months
Other outcomes:
measure: To quantify the objective response rate (ORR) of ORIN1001 alone and in combination with Abraxane
timeFrame: Baseline up to approximately 2 years
measure: To quantify the difference in the objective response rate (ORR) in relapsed refractory metastatic breast cancer showing potentially response-predictive aberrations of MYC and other genes under ORIN1001 alone or in combination with Abraxane
timeFrame: Baseline up to approximately 2 years
measure: To measure the response duration in patients receiving ORIN1001 alone and in combination with Abraxane.
timeFrame: Baseline up to approximately 2 years
measure: To quantify the difference in the duration of response in relapsed refractory metastatic breast cancer showing potentially response-predictive aberrations of MYC and other genes under ORIN1001 alone or in combination with Abraxane
timeFrame: Baseline up to approximately 2 years
measure: To measure the time to response in patients receiving ORIN1001 alone and in combination with Abraxane.
timeFrame: Baseline up to approximately 2 years
measure: To quantify the difference in the time to response in relapsed refractory metastatic breast cancer showing potentially response-predictive aberrations of MYC and other genes under ORIN1001 alone or in combination with Abraxane.
timeFrame: Baseline up to approximately 2 years
measure: To measure the duration of progression free survival (PFS) in patients receiving ORIN1001 alone and in combination with Abraxane
timeFrame: Baseline up to approximately 2 years
measure: To quantify the difference in the progression free survival (PFS) in relapsed refractory metastatic breast cancer showing potentially response-predictive aberrations of MYC and other genes under ORIN1001 alone or in combination with Abraxane.
timeFrame: Baseline up to approximately 2 years
measure: To measure the duration of overall survival (OS) under treatment with ORIN1001 alone and in combination with Abraxane.
timeFrame: Baseline up to approximately 2 years
measure: To quantify the difference in overall survival (OS) in relapsed refractory metastatic breast cancer showing potentially response-predictive aberrations of MYC and other genes under ORIN1001 alone or in combination with Abraxane
timeFrame: Baseline up to approximately 2 years
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Burbank
country: United States
facility: UCLA Health Burbank Specialty Care
state: California
city: Laguna Hills
country: United States
facility: UCLA Health Laguna Hills Cancer Care
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center (UCIMC) - Chao Family Comprehensive Cancer Center
state: California
city: Westwood
country: United States
facility: University of California Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center (JCCC) - Oncology Center - Westwood
state: California
city: Denver
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Highlands Ranch
country: United States
facility: Highlands Ranch Hospital
state: Colorado
city: Lone Tree
country: United States
facility: University of Colorado Lone Tree Medical Center
state: Colorado
city: Miami
country: United States
facility: University of Miami Hospital and Clinics - Sylvester Comprehensive Cancer Center
state: Florida
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Kansas
country: United States
facility: St Lukes Cancer Institute
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center (RPCCC) (Roswell Park Cancer Institute (RPCI))
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health
state: New York
city: New Hyde Park
country: United States
facility: Northwell Heath Cancer Institute
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine Medical Center
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Mothaffar F Rimawi, MD
role: PRINCIPAL_INVESTIGATOR
References: