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

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ClinicalTrials.gov Identifier: NCT03950570
Recruitment Status : Not yet recruiting
First Posted : May 15, 2019
Last Update Posted : May 15, 2019
Sponsor:
Information provided by (Responsible Party):
Shanghai Fosun Pharmaceutical Development Co, Ltd.

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

Condition or disease Intervention/treatment Phase
Solid Tumor Breast Cancer Metastatic Drug: Paclitaxel Phase 1

Detailed Description:
This is a first in human, Phase 1, open label, dose escalation and dose expansion study that consists of two stages: 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 paclitaxel given intravenously at 175 mg/m2 in up to 18 subjects with relapsed refractory metastatic breast cancer (TNBC, MYC+, or ER+ HER2-) . An expansion stage of ORIN1001 alone (Cohort A: TNBC) and in combination with paclitaxel (Cohorts B: MYC+; Cohort C: ER+ HER2-, and Cohort D: TNBC) to estimate efficacy in up to 120 subjects with relapsed refractory.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open Label, Dose-Escalation and Expansion Study of Oral ORIN1001 With and Without Chemotherapy in the Treatment of Subjects With Solid Tumors
Estimated Study Start Date : May 25, 2019
Estimated Primary Completion Date : May 29, 2020
Estimated Study Completion Date : November 29, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Paclitaxel

Arm Intervention/treatment
Experimental: Dose Escalation

Relapsed refractory metastatic breast cancer who are triple negative and treated with single agent ORIN1001.

Relapsed refractory metastatic breast cancer that are MYC+ and treated with combination.

Drug: Paclitaxel

The doses of ORIN 1001 in both dose escalation and dose expansion will be 100 mg, 200 mg, 400 mg, 600 mg,800mg, 1,000 mg, 1,300 mg, 1,500 mg The dose of paclitaxel will be constant at 175 mg/m2 given intravenously every three weeks for the dose escalation and dose expansion.

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).

Other Name: ORIN1001

Experimental: Dose Expansion

Relapsed refractory metastatic breast cancer that are ER+ HER2- and treated with combination.

Relapsed refractory metastatic breast cancer that are Triple Negative and treated with combination

Drug: Paclitaxel

The doses of ORIN 1001 in both dose escalation and dose expansion will be 100 mg, 200 mg, 400 mg, 600 mg,800mg, 1,000 mg, 1,300 mg, 1,500 mg The dose of paclitaxel will be constant at 175 mg/m2 given intravenously every three weeks for the dose escalation and dose expansion.

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).

Other Name: ORIN1001




Primary Outcome Measures :
  1. 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 [ Time Frame: From first dose up to 21 days after last dose ]
    To determine the safety of the maximal tolerated dose/ recommendeded 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).

  2. 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 [ Time Frame: 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).

  3. 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 [ Time Frame: 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).

  4. To evaluate the safety and tolerability of daily ORIN1001 when administered orally in combination with paclitaxel given intravenously at 175 mg/m2 once every three weeks in the dose escalation and expansion stages of the study [ Time Frame: From first dose up to 21 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 :
  1. To evaluate the peak concentrations (Cmax) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 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 paclitaxel.

  2. To evaluate the time to peak concentrations (Tmax) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 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 paclitaxel.

  3. 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 paclitaxel. [ Time Frame: 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 paclitaxel.

  4. To evaluate the last time point with a quantifiable concentration (AUClast) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 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 paclitaxel.

  5. To evaluate the plasma concentration end of a dosing interval (Ctau) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 2 months ]
    Determine the dose-dependent plasma concentrations (Cmax) of ORIN1001 as single agent or in combination with paclitaxel at the end of a dosing interval (Ctau), where tau is 24 hours for once daily dosing.

  6. To evaluate the average plasma concentration (Cav) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 2 months ]
    Determine the average plasma concentration (Cav) of ORIN1001 as single agent or in combination with paclitaxel during the dosing interval.

  7. To evaluate the minimum plasma concentrations (Cmin) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 2 months ]
    Determine the the minimum plasma concentrations (Cmin) reached by ORIN1001 as single agent or in combination with paclitaxel prior to administration of a second dose.

  8. To evaluate the elimination constant (λz) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 2 months ]
    Determine the dose-dependent plasma elimination constant (λz) for ORIN1001 as a single agent or in combination with paclitaxel.

  9. To evaluate the terminal half-life (T1/2) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 2 months ]
    Determine the dose-dependent terminal plasma half-life of ORIN1001 (T1/2) as a single agent or in combination with paclitaxel.

  10. To evaluate the plasma clearance (CL/f) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 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 paclitaxel.

  11. To evaluate the volume of distribution (Vz/f) of ORIN1001 after oral administration as a single agent and in combination with paclitaxel. [ Time Frame: 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 paclitaxel.


Other Outcome Measures:
  1. To quantify the objective response rate (ORR) of ORIN1001 alone and in combination with paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To quantify the proportion of patients with an objective tumor response as defined by RECIST 1.1 response criteria (SD, PR, CR).

  2. 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 paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To quantify the proportion of patients with an objective tumor response as defined by RECIST 1.1 response criteria (SD, PR, CR).

  3. To measure the response duration in patients receiving ORIN1001 alone and in combination with paclitaxel. [ Time Frame: Baseline up to approximately 2 years ]
    To measure the duration of response from the time point of first established response (SD, PR, CR) until the time of documented tumor progression.

  4. 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 paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the duration of response from the time point of first established response (SD, PR, CR) until the time of documented tumor progression.

  5. To measure the time to response in patients receiving ORIN1001 alone and in combination with paclitaxel. [ Time Frame: Baseline up to approximately 2 years ]
    To measure the time from cycle 1 day 1 dose to the time of first documentation of tumor response (SD, PR, CR).

  6. 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 paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the time from cycle 1 day 1 dose to the time of first documentation of tumor response (SD, PR, CR).

  7. To measure the duration of progression free survival (PFS) in patients receiving ORIN1001 alone and in combination with paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the time from cycle 1 day 1 dose administration to the time of documented disease progression or death from any cause.

  8. 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 paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the time from cycle 1 day 1 dose administration to the time of documented disease progression or death from any cause.

  9. To measure the duration of overall survival (OS) under treatment with ORIN1001 alone and in combination with paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the duration of overall survival (OS) which is the time from Cycle 1 day 1 until death from any cause.

  10. 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 paclitaxel [ Time Frame: Baseline up to approximately 2 years ]
    To measure the duration of Overall Survival (OS) which is the time from Cycle 1 day 1 until death from any cause.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 paclitaxel:

-Males or females with relapsed refractory metastatic breast cancer (TNBC, MYC+, 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, and 3. MYC+ breast cancer for whom there are no available therapies that confer a clinical benefit 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 4 weeks or 5 times the plasma half-life of the drug, whichever is shorter; c.Prior radiotherapy within 4 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 mestastases 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 paclitaxel 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)

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Responsible Party: Shanghai Fosun Pharmaceutical Development Co, Ltd.
ClinicalTrials.gov Identifier: NCT03950570     History of Changes
Other Study ID Numbers: ORIN1001-001
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: May 15, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action