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A Monotherapy in Subjects With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04221204
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
3D Medicines (Sichuan) Co., Ltd.

Brief Summary:
A Phase 1 Study of the Safety, Tolerability, Pharmacokinetics Profiles, and Preliminary Efficacy of 3D185 Monotherapy in Subjects with Advanced Solid Tumors

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Drug: Highly selective FGFR1-3 inhibitor Phase 1

Detailed Description:

Subjects with advanced solid tumors who have no available standard therapy or who have failed standard therapies.

This is an open-label, global multicenter, dose-escalation phase 1 study of safety, tolerability, preliminary PK profile, and preliminary efficacy of 3D185 monotherapy in subjects with advanced solid tumors.

The starting dose in this dose-escalation study is 25 mg, and the preset 7 dose-escalation cohorts are 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg, respectively.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Intervention Model: Sequential Assignment
Intervention Model Description: The starting dose in this dose-escalation study is 25 mg, and the preset 7 dose-escalation cohorts are 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg, respectively.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of the Safety, Tolerability, Pharmacokinetics Profiles and Preliminary Efficacy of 3D185 Monotherapy in Subjects With Advanced Solid Tumors
Actual Study Start Date : September 1, 2019
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : September 30, 2020

Arm Intervention/treatment
Experimental: Open-Label, Dose-Escalation

To explore the maximum tolerated dose (MTD) and the recommended dose for subsequent studies (RPTD) of 3D185 monotherapy in subject with advanced solid tumors.

The starting dose in this dose-escalation study is 25 mg, and the preset 7 dose-escalation cohorts are 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg, respectively. This study adopts a combination of accelerated titration and i3+3[1] for dose escalation. All subjects in each cohort will receive a single oral dose of 3D185, followed by a 7-day washout period (i.e. single-dose PK study period). Then, subjects will receive consecutive daily doses (Once daily [QD], 28 days/cycle) until disease progression, death, unacceptable toxicity, or withdraw of informed consent, whichever comes first.

Drug: Highly selective FGFR1-3 inhibitor
All subjects in each cohort will receive a single oral dose of 3D185, followed by a 7-day washout period (i.e. single-dose PK study period). Then, subjects will receive consecutive daily doses (Once daily [QD], 28 days/cycle) until disease progression, death, unacceptable toxicity, or withdraw of informed consent, whichever comes first. The dose limiting toxicity (DLT) evaluation period includes the single-dose PK study period and the first treatment cycle (within 35 days after the first dose). The enrolled subjects will be sequentially assigned to the planned dose cohorts according to the protocol and receive 3D185 treatment to observe the occurrence of DLT.




Primary Outcome Measures :
  1. Safety Evaluation: frequency and severity of AEs [ Time Frame: 24 months ]
    Evaluated based on the frequency and severity of AEs according to NCI CTCAE v4.03.

  2. Tolerability Evaluation: frequency and severity of AEs [ Time Frame: 24 hours ]
    based on the frequency and severity of AEs according to NCI CTCAE v4.03.


Secondary Outcome Measures :
  1. Efficacy evaluation: Complete Response [ Time Frame: 24 months ]
    Per RECIST version 1.1 criteria in Solid tumors v 1.1 (RECIST) assessed by investigator

  2. Pharmacokinetics (PK) evaluation: Cmax (mg/L) [ Time Frame: 24 months ]
    The test of PK samples will be performed by central laboratory. The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  3. PK evaluation: Tmax (minutes) [ Time Frame: 24 months ]
    The test of PK samples will be performed by central laboratory. The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  4. PK evaluation: AUC0-24 h, AUC0-96 h, AUC0-∞, [ Time Frame: 24 months ]
    The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  5. PK evaluation: t1/2 [ Time Frame: 24 months ]
    The test of PK samples will be performed by central laboratory. The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  6. PK evaluation: Clearance [ Time Frame: 24 months ]
    The test of PK samples will be performed by central laboratory. The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  7. PK evaluation: Vd. [ Time Frame: 24 months ]
    The test of PK samples will be performed by central laboratory. The PK parameters will be calculated using standard non-compartment models and WinNonlin® Professional 6.4 or higher version (Certara, Princeton, NJ, USA) or SAS® 9.3 or higher version (SAS Institute, Inc., Cary, North Carolina) to fully reflect the drug absorption, distribution and elimination characteristics in the human body. The interim PK parameters will be calculated using the planned blood collection time, and the final PK parameters will be calculated using the actual blood collection time.

  8. Progressive Disease evaluation [ Time Frame: 24 months ]
    assessed by analyzing the change in serum phosphate levels relative to baseline level over time (Serum biochemistry test).

  9. Efficacy evaluation: Partial Response [ Time Frame: 24 months ]
    Per RECIST version 1.1 criteria in Solid tumors v 1.1 (RECIST) assessed by investigator

  10. Efficacy evaluation: Stable Disease [ Time Frame: 24 months ]
    Per RECIST version 1.1 criteria in Solid tumors v 1.1 (RECIST) assessed by investigator

  11. Efficacy evaluation: Disease Progression [ Time Frame: 24 months ]
    assessed by analyzing the change in serum phosphate levels relative to baseline level over time (Serum biochemistry test).

  12. Objective Response Rale (ORR) (CR+PR) [ Time Frame: 24 months ]
    Per RECIST version 1.1 criteria in Solid tumors v 1.1 (RECIST) assessed by investigator

  13. disease control rate (DCR) (CR+PR+SD) [ Time Frame: 24 months ]
    Per RECIST version 1.1 criteria Per RECIST version 1.1 criteria in Solid tumors v 1.1 (RECIST) assessed by investigator



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Study Population:

In the study, male or female adult subjects ≥ 18 years of age, with advanced solid tumors with no prior standard therapy or failed to establish standard therapies are eligible.

Inclusion Criteria:

  1. Subjects must be male or female and ≥ 18 years of age on the day of enrollment.
  2. Subjects must have a histological diagnosis of locally advanced or metastatic malignant solid tumors. Subjects must have failed or have been intolerant to established standard therapies, or standard therapies did not exist or were no longer effective for a given tumor type, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds.
  3. Subjects must have at least one evaluable lesion (according to RECIST 1.1, see Appendix 1);
  4. ECOG Performance Status of 0 or 1.
  5. Life expectancy ≥ 12 weeks.
  6. Subjects must have normal levels of total serum calcium and total phosphate.
  7. Subjects must have adequate organ and bone marrow function (no hematopoietic growth factor, blood transfusion, or platelet therapy within 1 week before the first dose):

    • CBC: neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 9.0 g/dL.
    • Liver function: total bilirubin ≤ 1.5 × ULN; ALT/AST ≤ 2.5 × ULN without liver metastasis; ALT/AST ≤ 5 × ULN with liver metastasis;
    • Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (for patients undergoing anticoagulant therapy. The Investigator will judge that the INR and APTT are within a safe and effective treatment range).
    • Renal function: serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 60 mL/min/1.73 m2 in the condition of creatinine level > ULN; urine protein qualitative ≤ 1 + (if ≥ 2+, 24 hours of urine protein test is required, if 24 hours urine protein <1 g, then allowed to enroll);
    • Adequate cardiac function left ventricular ejection fraction (LVEF) > 50% for 2 dimensional cardiac ultrasound;
  8. Subjects must have signed and dated an IRB/IEC approved written informed consent form that under regulatory and institutional guidelines, and this must be obtained before the performance of any protocol-related procedures.

Exclusion Criteria:

Subjects who meet any of the following criteria should be excluded from the study:

  1. Subjects who received other investigational products or devices in other clinical trials within 4 weeks before the first dose;
  2. Subjects who received anti-tumor therapy (except for mitomycin, nitrosourea, and fluorouracil oral drugs) within 4 weeks before the first dose, including but not limited to chemotherapy, radiotherapy (palliative radiotherapy is completed at least 2 weeks before the first dose can enroll), targeted therapy or immunotherapy.

    Note: Mitomycin and nitrosourea have been treated within 6 weeks after the last dose; oral fluorouracil such as tegafur and capecitabine has been treated within 2 weeks after the last dose.

  3. Subjects who previously received FGFR1-3 specific inhibitor therapy.
  4. Subjects who have previous toxicity of anti-tumor therapy that has not been returned to level 0 or 1. (Alopecia, chemotherapy-induced peripheral neurotoxicity and ototoxicity ≤ Grade 2 can enroll);
  5. Subjects who received a CYP3A4 and/or CYP2C8 strong inhibitor or a CYP3A4 strong inducer (see Appendix 6) within 7 days prior to the first dose, and need to continue using these drugs;
  6. Subjects who have any of the following eye diseases/conditions:

    • History of retinal pigment epithelial detachment (RPED);
    • History of laser treatment or intraocular injection for macular degeneration;
    • History of dry or wet age-related macular degeneration;
    • History of retinal vein occlusion (RVO);
    • History of retinal degenerative diseases;
    • History of chorioretinal lesions;
  7. Subjects who received clinical intervention for biliary obstruction 14 days prior to the first dose or the Investigator judges that the symptoms had not resolved or required anti-infective treatment.
  8. Subjects who have gastrointestinal disorders that will affect oral administration or the Investigator judges that the absorption of 3D185 will be interfered.
  9. Subjects underwent major surgery (except biopsy), or the surgical incision has not completely healed within 4 weeks prior to the first dose.
  10. Subjects who had clinically uncontrollable pleural effusion, ascites, or pericardial effusion within 2 weeks prior to the first dose.
  11. Subjects who have symptomatic brain metastases or spinal cord compression. Subjects who have previously treatment for brain metastases, if the clinical condition is stable and imaging evidence does not show disease progression within 4 weeks prior to the first dose, and do not need corticosteroid treatment within 2 weeks prior to the first dose, can enroll.
  12. Subjects who have active bacterial or fungal infections (CTCAE ≥ 2) that required systemic treatment within 14 days prior to the first dose.
  13. Subjects who have active HBV infection (Tests should include assessment of HBsAg and HBc IgG antibody. If one parameter is positive, determine HBV-DNA to confirm acute infection. Patients with positive results for HBsAg and/or HBV-DNA are considered active HBV infection) and/or active HCV infection (HCV antibody testing positive);
  14. Subjects who have clinically significant cardiovascular diseases that occurred 6 months prior to enrollment. Cardiovascular diseases include, but not limited to follows:

    • Acute myocardial infarction;
    • Severe/unstable angina;
    • Cerebrovascular accident or transient ischemic attack;
    • Congestive heart failure (New York Heart Association > Class II, see Appendix 3);
    • Arrhythmias that require antiarrhythmic treatment except for beta blockers or digoxin;
    • Repeated ECG with QTc interval > 450 ms;
    • High blood pressure that cannot be controlled by antihypertensive drugs (systolic blood pressure > 150 mm Hg, diastolic blood pressure > 100 mmHg).
  15. Subjects who have clinically significant abnormal serum electrolytes (Patients must have corrected calcium and phosphate < institutional ULN).
  16. Subjects who are receiving warfarin (low-dose warfarin as 2 mg/day is acceptable); or receiving antiplatelet anticoagulant therapy (aspirin at dose ≥300 mg/day, clopidogrel at dose ≥75 mg/day).
  17. Female subjects in pregnancy or lactation. Male subjects or female subjects at reproductive ages who are unwilling to receive effective contraceptive measures.
  18. Subjects who are judged by the Investigator to be unsuitable for this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221204


Contacts
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Contact: Silong Xiang, M.D. ( 86)15901312398 silong.xiang@3dmedcare.com
Contact: Regina Jones, B.S. 9197039920 ext 9197039920 jones@3dmedcare.com

Locations
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China
Affiliated Hospital of Military academy of medical sciences Recruiting
Beijing, China, 100071
Contact: Xu Jianming, Dr.    86-10-66947176    jmxu2003@163.com   
Sponsors and Collaborators
3D Medicines (Sichuan) Co., Ltd.
Investigators
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Study Director: Er Xiao 3D Medicines (Beijing) Co., Ltd.
  Study Documents (Full-Text)

Documents provided by 3D Medicines (Sichuan) Co., Ltd.:
Study Protocol  [PDF] November 18, 2019


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Responsible Party: 3D Medicines (Sichuan) Co., Ltd.
ClinicalTrials.gov Identifier: NCT04221204    
Other Study ID Numbers: 3D185-CN-001
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: December 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
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Neoplasms