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Dose Escalation and Dose Expansion Study of CPO-100 in Patients 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: NCT04931823
Recruitment Status : Recruiting
First Posted : June 18, 2021
Last Update Posted : December 19, 2022
Sponsor:
Collaborator:
CSPC ZhongQi Pharmaceutical Technology Co., Ltd.
Information provided by (Responsible Party):
Conjupro Biotherapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE June 4, 2021
First Posted Date  ICMJE June 18, 2021
Last Update Posted Date December 19, 2022
Actual Study Start Date  ICMJE March 24, 2021
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 6, 2022)
  • Part A-1: Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: At the end of cycle 1 (each cycle is 28 days) ]
    Incidence of dose-limiting toxicities (DLT) during the DLT evaluation period. DLTs assessed per CTCAE v5.0, include grade ≥ 4 neutropenia, thrombocytopenia, anemia; grade ≥ 3 febrile neutropenia, nausea, vomiting, diarrhea, skin rash, fatigue, infusion reaction; any other grade ≥ 2 non-hematologic toxicity judged to be dose limiting; and treatment delay >14 days due to unresolved toxicities.
  • Part A-2: Number of subjects with Dose Limiting Toxicities (DLTs) when prophylactic use of G-CSF is allowed during Cycle 1 [ Time Frame: At the end of cycle 1 (each cycle is 28 days) ]
    Incidence of dose-limiting toxicities (DLT) during the DLT evaluation period. DLTs assessed per CTCAE v5.0, include grade ≥ 4 neutropenia, thrombocytopenia, anemia; grade ≥ 3 febrile neutropenia, nausea, vomiting, diarrhea, skin rash, fatigue, infusion reaction; any other grade ≥ 2 non-hematologic toxicity judged to be dose limiting; and treatment delay >14 days due to unresolved toxicities.
  • Part B: Dose Expansion - Incidence and severity of Adverse Events [ Time Frame: Screening to up to 4 years ]
    Incidence and severity of Adverse Events per CTCAE v5.0, including changes of Clinical Laboratory Values, Physical Exams, Vital Signs, Weight, Eastern Cooperative Oncology Group (ECOG) and ECG from baseline. Dosing delays and dosing intensity.
Original Primary Outcome Measures  ICMJE
 (submitted: June 11, 2021)
  • Part A: Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: At the end of cycle 1 (each cycle is 28 days) ]
    Incidence of dose-limiting toxicities (DLT) during the DLT evaluation period. DLTs assessed per CTCAE v5.0, include grade ≥ 4 neutropenia, thrombocytopenia, anemia; grade ≥ 3 febrile neutropenia, nausea, vomiting, diarrhea, skin rash, fatigue, infusion reaction; any other grade ≥ 2 non-hematologic toxicity judged to be dose limiting; and treatment delay >14 days due to unresolved toxicities.
  • Part B: Dose Expansion - Incidence and severity of Adverse Events [ Time Frame: Screening to up to 4 years ]
    Incidence and severity of Adverse Events per CTCAE v5.0, including changes of Clinical Laboratory Values, Physical Exams, Vital Signs, Weight, Eastern Cooperative Oncology Group (ECOG) and ECG from baseline. Dosing delays and dosing intensity.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2021)
  • Area Under the Curve (AUC0-t) for CPO-100 [ Time Frame: 0, .5, 1, 2, 3, 4, 6, 8, 24, 48 and 72 hours (Day1) and Day 15 ]
    Area under the plasma concentration curve (AUC0-t) will be from time zero to last quantifiable concentration.
  • Area Under the Curve (AUC0-∞) for CPO-100 [ Time Frame: 0, .5, 1, 2, 3, 4, 6, 8, 24, 48 and 72 hours (Day1) ]
    Area under the plasma concentration curve (AUC0-∞) will be from time zero to infinity.
  • Cmax for CPO-100 [ Time Frame: 0, .5, 1, 2, 3, 4 6, 8, 24, 48 and 72 hours (Day 1) and Day 15 ]
    Cmax will be estimated from the maximum post-dose concentration recorded for each patient.
  • Tmax for CPO-100 [ Time Frame: Time Frame: 0, .5, 1, 2, 3, 4 6, 8, 24, 48 and 72 hours (Day 1) and Day 15 ]
    Tmax will be estimated from the relative time of the maximum post-dose concentration recorded for each patient.
  • Overall response rate (ORR) [ Time Frame: At the end of every 28 day cycle for up to 4 years ]
    The proportion of patients achieving a partial response (PR) or complete response (CR) per RECIST 1.1 supplemented by recommendations from the Prostate Cancer Clinical Trials Working Group 3 (PCCTWG3).
  • Disease control rate (DCR) [ Time Frame: At the end of every 28 day cycle for up to 4 years ]
    The proportion of patients achieving a stable disease (SD), PR, CR per RECIST 1.1 supplemented by recommendations from the Prostate Cancer Clinical Trials Working Group 3 (PCCTWG3).
  • Duration of Response (DoR) [ Time Frame: From first PR or CR until disease progression or death up to 4 years ]
    Time from first PR or CR until progression of death using definition of PR and CR per (RECIST) 1.1 supplemented by recommendations from the Prostate Cancer Clinical Trials Working Group 3 (PCCTWG3).
  • Progression-Free Survival (PSF) [ Time Frame: From first dose until documented disease progression or death up to 4 years ]
    Time from first dose until disease progression or death using RECIST 1.1 supplemented by recommendations from the Prostate Cancer Clinical Trials Working Group 3 (PCCTWG3) for progression.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalation and Dose Expansion Study of CPO-100 in Patients With Advanced Solid Tumors
Official Title  ICMJE A Phase 1, Multicenter, Single Agent Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Evidence of Antitumor Activity of CPO-100 in Adult Patients With Advanced Solid Tumors
Brief Summary This is a Phase 1, multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary evidence of antitumor activity of CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) in adult patients with advanced solid tumors.
Detailed Description

The study has three parts. Part A-1 is a dose-escalation phase with a modified "3+3" design in patients with metastatic or unresectable advanced solid tumors to evaluate the safety, tolerability and pharmacokinetics (PK) as a single agent. Two patients will be enrolled at each of the first 2 dose levels and observed for safety during the first cycle. If there are no ≥Grade 2 treatment emergent adverse events (TEAE) that are clinically significant and attributed to the study drug as assessed by the investigator during Cycle 1 for any of the patients in the first two dose levels, the 3rd dose level and beyond will follow the traditional 3+3 design. Dose escalation during the "3+3" period for each subsequent cohort of patients will be guided by the incidence of CPO-100-related adverse events (AE) as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) CTCAE v5.0 in the first 4 weeks of dosing [the Dose Limiting Toxicity (DLT) evaluation period].

In Part A-2, the starting dose for this part will be 45 mg/m2. This dose was established in Part A-1 as being that dose at which the use of Granulocyte-colony stimulating factor ()G-CSF is indicated given that the only Grade 3 treatment-related adverse events noted were related to neutropenia and was well managed with G-CSF support. Prophylactic use of G-CSF will be permitted in Cycle 1 based on the investigator judgement.

This additional intervention of primary prophylaxis will be explored in order to determine if the risk of febrile neutropenia (FN) under these circumstances is reduced. Dose escalation during the 3+3 period for each subsequent cohort of patients will be guided by the incidence of CPO-100-related adverse events (AE) as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 in the first 4 weeks of dosing (the DLT evaluation period).

After the Maximum Tolerated Dose (MTD) of weekly dosing schedule has been established, a recommended Phase 2 dose will be selected based on evaluation of the PK, and safety and tolerability profile on all available Part A study data by the Safety Review Committee (SRC). The selection of the Recommended Phase 2 Dose (RP2D) will consider all available clinical and non-clinical CPO-100 data as well as relevant docetaxel published data.

Part B expansion phase will further evaluate the safety and tolerability as well as the preliminary antitumor activity at the selected RP2D. Four cohorts of patients are included in Part B:

  • Cohort 1: taxane naïve advanced/metastatic gastric, head and neck, lung, and ovarian cancers
  • Cohort 2: taxane naïve advanced/metastatic breast cancer
  • Cohort 3: taxane naïve advanced /metastatic prostate cancer
  • Cohort 4: advanced/metastatic breast or ovarian cancer who have either progressed on a taxane or have developed progressive disease within 6 months of receiving a taxane.

The taxane naïve patient population is defined as patients who have not received taxane or taxane-based therapies for their metastatic diseases or patients who had suboptimal taxane exposure defined as having received less than 2 cycles of taxane or taxane-based therapies due to intolerability for their metastatic diseases. Patients who have received taxane or taxane-based therapies for their neoadjuvant treatment or patients who have received taxane or taxane-based therapies for their adjuvant treatment without disease progression during treatment are also considered taxane naïve, as long as they have not received taxane or taxane-based therapies to treat the metastatic diseases.

It is estimated that approximately 60 patients can be enrolled in Parts A-1 and A-2. The exact number of patients will depend on the number of dose levels tested. A total of 60 patients, 15 patients in each cohort will be enrolled in Part B.

The total duration of the study is estimated to be approximately 5 years. Patients may continue receiving CPO-100 until criteria for withdrawal are met. Patients deriving clinical benefit may continue to receive study medication for as long as they are benefiting from treatment. In the event the study closes or terminates while patients are still benefiting from and receiving CPO-100, every effort will be made to continue drug supply.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Modified "3+3" dose escalation design followed by dose expansion at the MTD (maximum tolerated dose).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor
Intervention  ICMJE Drug: CPO-100
Docetaxel albumin-bound
Other Name: DTX-HSA
Study Arms  ICMJE
  • Experimental: Part A-1: Dose Escalation
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks).
    Intervention: Drug: CPO-100
  • Experimental: Part A-2: Dose escalation
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) with the option to administer G-CSF in cycle one. Starting dose will be 45 mg/m2.
    Intervention: Drug: CPO-100
  • Experimental: Part B: Cohort 1
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) at the recommended Phase 2 dose (X mg/m2) in 15 patients with taxane naïve advanced solid tumors of gastric, head and neck, lung, and ovarian.
    Intervention: Drug: CPO-100
  • Experimental: Part B: Cohort 2
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) at the recommended Phase 2 dose (X mg/m2) in 15 patients with taxane naïve advanced breast cancer.
    Intervention: Drug: CPO-100
  • Experimental: Part B: Cohort 3
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) at the recommended Phase 2 dose (X mg/m2) in 15 patients with taxane naïve advanced prostate cancer.
    Intervention: Drug: CPO-100
  • Experimental: Part B: Cohort 4
    CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) at the recommended Phase 2 dose (X mg/m2) in 15 patients with either ovarian or/and breast cancer who have failed prior taxane treatment (ie, either progressed on a taxane regimen or within 6 months of receiving a taxane regimen).
    Intervention: Drug: CPO-100
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 6, 2022)
126
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2021)
142
Estimated Study Completion Date  ICMJE March 1, 2025
Estimated Primary Completion Date March 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria - Parts A-1, A-2, and B:

  1. Presence of a pathologically documented (histology or cytology) locally advanced or metastatic solid tumor cancer.
  2. Patients has failed at least 2 lines of conventional systemic therapy or have no other standard of care therapies available for their cancer. Prostate cancer patients should have received adenosine triphosphate (ADT) alone,(GnRH agonist, GnRH antagonist, or surgical orchiectomy and a pathway targeted agent such as abiraterone, enzalutamide, etc (castration-resistant prostate cancer). M1 disease must be present (not just biochemical recurrence).
  3. Male or female patients18 years of age or older.
  4. ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0, 1 or 2
  5. Having at least one measurable target lesion present and documented by RECIST 1.1 for each cancer other than prostate cancer. Patients with prostate cancer may be enrolled with non-measurable disease providing the patient with a prostate-specific antigen (PSA) increase that is ≥25% and ≥2 ng/mL above the nadir, which is confirmed by a second value ≥3 weeks later, or 2 or more new bone lesions on imaging.
  6. Adequate major system function defined as:

    1. Bone marrow reserve:

      Absolute neutrophil count (ANC) ≥1.5 x109/L Platelet count ≥ 100 x109/L Hemoglobin ≥9 g/dL without transfusion (the patient needs to be transfusion independent)

    2. Hepatic function:

      Total bilirubin ≤ upper limit of normal (ULN) (unless the subject has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of total bilirubin); And aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 x ULN with alkaline phosphatase ≤2.5 x ULN.

    3. Renal function:

      Normal serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated creatinine clearance ≥50 mL/min. (Cockcroft - Gault formula)

    4. Coagulation:

    Adequate coagulation parameters defined as International Normalization Ratio (INR) ≤2.

  7. Adequate methods of contraception for female patients of reproductive potential during the study and for at least 6 months following last dose. Male patients with female partners of childbearing potential and women patients of childbearing potential are required to use two forms of acceptable contraception, including 1 barrier method, during their participation in the study and for at least 3 months following last dose. Male patients must also refrain from donating sperm during their participation in the study.
  8. Life expectancy ≥3 months.
  9. Willingness and ability to comply with study and follow-up procedures.
  10. Ability to understand the nature of this study and give written informed consent.

Additional Inclusion Criteria for the dose expansion cohort - Part B

  1. Pathologically confirmed (histology or cytology) of the following cancer types:

    1. Cohort 1: taxane naïve advanced/metastatic gastric cancer, lung cancer, head and neck cancer, or ovarian cancer;
    2. Cohort 2: taxane naïve advanced/metastatic breast cancer;
    3. Cohort 3: taxane naïve advanced/metastatic prostate cancer.
    4. Cohort 4: advanced/metastatic breast or ovarian cancer patients who have either progressed on a taxane or have developed progressive disease within 6 months of receiving a taxane;
  2. With the exception of Cohort 4 above, taxane naïve patients must not have received taxane or taxane based therapies for their metastatic diseases. Patients who had suboptimal taxane exposure defined as having received less than 2 cycles of taxane or taxane based therapies due to intolerability for their metastatic diseases, patients who have received taxane or taxane based therapies for their neoadjuvant treatment or patients who have received taxane or taxane based therapies for their adjuvant treatment without disease progression during treatment are also considered taxane naïve, as long as they have not received taxane or taxane based therapies to treat the metastatic diseases.

Exclusion Criteria - Part A and B

  1. Most recent chemotherapy ≤14 days or have residual NCI CTCAE greater than Grade 1 chemotherapy-related side effects, with the exception of alopecia.
  2. Use of any experimental drug ≤28 days or 5 half-lives (whichever is shorter) prior to the first dose of CPO-100. For study drugs for which 5 half-lives is ≤28 days, a minimum of 14 days between termination of the study drug and administration of CPO-100 is required.
  3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89 and lutetium 177) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.
  4. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement.
  5. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks previously and there is no evidence of central nervous system disease progression, and no requirement for chronic corticosteroid therapy.
  6. Leptomeningeal metastases or spinal cord compression due to disease.
  7. Known serious hypersensitivity reactions to docetaxel or life-threatening toxicity due to prior exposure to docetaxel
  8. Pregnant or lactating.
  9. Acute or chronic liver, renal, or pancreatic disease that in the opinion of the investigator would put the patient at unjustified increased risk by participating in this study or could interfere with the interpretation of the study results.
  10. Other systemic disease that in the opinion of the investigator would put the patient at unjustified increased risk by participating in this study or could interfere with the interpretation of the study results.
  11. Any of the following cardiac diseases currently or within the last 6 months:

    • Left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
    • Corrected QT (QTc) interval >470 ms (average of 3 tracings) on screening electrocardiogram (ECG)
    • Unstable angina pectoris
    • Congestive heart failure according to the New York Heart Association (NYHA) ≥ Grade 2)
    • Acute myocardial infarction
    • Conduction abnormality not controlled with pacemaker or medication
    • Significant ventricular or supraventricular arrhythmias. (Patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible.)
  12. Inadequately controlled hypertension (ie, systolic blood pressure (SBP) >180 mmHg or diastolic blood pressure (DBP) >100 mmHg). Subjects with values above these levels must have their blood pressure (BP) controlled with medication prior to starting treatment.
  13. Serious active infection at the time of treatment, or another serious underlying medical condition that that in the judgment of the investigator would impair the ability of the patient to receive protocol treatment.
  14. HIV positive test within 8 weeks of screening. HIV positive patients with T-cell (CD4+) counts ≥350 cells/mL and not receiving treatment or does not plan to be treated with antiretroviral medication will be eligible for the study. Testing for seropositive status during screening will be at the discretion of the investigator in patients without previously reported results.
  15. Active hepatitis B, or hepatitis C infection.

    • Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at Screening.
    • Patients with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA level is below the limit of detection by PCR) may be enrolled into the study. Subjects with controlled infections must undergo periodic monitoring of HBV DNA per treating physician.
    • Patients with hepatitis C (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) may be enrolled into the study. Patients with controlled infections must undergo periodic monitoring of HCV RNA per treating physician.
  16. Presence of other active cancers, or history of treatment for invasive cancer ≤3 years. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
  17. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
  18. Routine use of corticosteroids or erythrocyte-stimulating factors as well as prophylactic use of colony-stimulating factors.
  19. Use of any strong CYP3A4 inhibitor or strong inducer drugs ≤28 days or 5 half-lives (whichever is shorter) prior to the first dose of CPO-100. For CYP3A4 inducer drugs for which 5 half-lives is ≤28 days, a minimum of 14 days between discontinuation of the drug and administration of CPO-100 is required.
  20. Use of herbal preparations/medications including, but are not limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. A minimum of 14 days between discontinuation of the herbal preparation/medications and administration of CPO-100 is required.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Officials 6093560210 Clinicaltrials.gov@cspcus.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04931823
Other Study ID Numbers  ICMJE CPO-100-US-101
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Undecided
Current Responsible Party Conjupro Biotherapeutics, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Conjupro Biotherapeutics, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE CSPC ZhongQi Pharmaceutical Technology Co., Ltd.
Investigators  ICMJE
Study Director: Study Officials Conjupro Biotherapeutics, Inc.
PRS Account Conjupro Biotherapeutics, Inc.
Verification Date December 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP