Dose Escalation and Dose Expansion Study of CPO-100 in Patients With Advanced Solid Tumors

Sponsor

Conjupro Biotherapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04931823

Collaborator

CSPC ZhongQi Pharmaceutical Technology Co., Ltd. (Industry)

142

Enrollment

Locations

Arms

47.2

Anticipated Duration (Months)

14.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, dose escalation 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. The second part of the study will further evaluate the safety and tolerability of as well as antitumor activity at the recommended dose from the dose escalation phase.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor	Drug: CPO-100	Phase 1

Detailed Description

This is a phase 1, multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary evidence of antitumor activity of CPO-100 administered via the patient port in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) in adult patients with advanced solid tumors.

The study has two parts. Part A is a dose-escalation phase with a modified "3+3" design in patients with metastatic or unresectable advanced solid tumors to determine the recommended phase 2 dose (RP2D) and schedule, and to evaluate the safety, tolerability and 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].

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 by the Safety Review Committee (SRC). The selection of the 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 up to 42 patients can be enrolled in Part A. 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 4 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 Design

Study Type:

Interventional

Anticipated Enrollment :

142 participants

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).Modified "3+3" dose escalation design followed by dose expansion at the MTD (maximum tolerated dose).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 24, 2021

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: Dose Escalation CPO-100 administered intravenously At Dose Level 1 & 2: 2 patients will be enrolled. Cohort(s) may be expanded up to 6 patients if a Dose Limiting Toxicity (DLT) occurs within the first 4 weeks after first dosing. At Dose Level 3 - 7: 3-6 patients will be enrolled. Cohort(s) will be expanded up to 6 patients if a DLT occurs within the first 4 weeks after first dosing. Dose escalation will end once the maximum tolerated dose (MTD) has been reached. Once the MTD is identified, a recommended Phase 2 dose (RP2D) will be chosen based on accumulated PK, safety data, and further assessed in Part B dose expansion cohorts in patients with advanced solid tumors.	Drug: CPO-100 Docetaxel albumin-bound Other Names: DTX-HSA
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.	Drug: CPO-100 Docetaxel albumin-bound Other Names: DTX-HSA
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.	Drug: CPO-100 Docetaxel albumin-bound Other Names: DTX-HSA
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.	Drug: CPO-100 Docetaxel albumin-bound Other Names: DTX-HSA
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).	Drug: CPO-100 Docetaxel albumin-bound Other Names: DTX-HSA

Outcome Measures

Primary Outcome Measures

Part A: Number of subjects with Dose Limiting Toxicities (DLTs) [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 [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.

Secondary Outcome Measures

Area Under the Curve (AUC0-t) for CPO-100 [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 [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 [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: 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) [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) [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) [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) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria - Part A and B:

Presence of a pathologically documented (histology or cytology) locally advanced or metastatic solid tumor cancer.
Patients has failed at least 2 lines of conventional systemic therapy or have no other standard of care therapies available for their cancer. For a prostate cancer patient, adenosine triphosphate (ADT) alone (GnRH agonist, GnRH antagonist, or surgical orchiectomy) would count towards a line of conventional systemic therapy.
Male or female patients18 years of age or older.
ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0, 1 or 2
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.
Adequate major system function defined as:
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)

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.

Renal function:

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

Coagulation:

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

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.
Life expectancy ≥3 months.
Willingness and ability to comply with study and follow-up procedures.
Ability to understand the nature of this study and give written informed consent.

Additional Inclusion Criteria for the dose expansion cohort - Part B

Pathologically confirmed (histology or cytology) of the following cancer types:
Cohort 1: taxane naïve advanced/metastatic gastric cancer, lung cancer, head and neck cancer, or ovarian cancer;
Cohort 2: taxane naïve advanced/metastatic breast cancer;
Cohort 3: taxane naïve advanced/metastatic prostate cancer.
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;
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

Most recent chemotherapy ≤14 days or have residual NCI CTCAE greater than Grade 1 chemotherapy-related side effects, with the exception of alopecia.
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.
Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 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.
Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement.
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.
Leptomeningeal metastases or spinal cord compression due to disease.
Known serious hypersensitivity reactions to docetaxel or life-threatening toxicity due to prior exposure to docetaxel
Pregnant or lactating.
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.
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.
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.)

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.
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.
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.
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.

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.
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
Routine use of corticosteroids or erythrocyte-stimulating factors as well as prophylactic use of colony-stimulating factors.
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles	Los Angeles	California	United States	75246
2	University of Colorado Denver	Denver	Colorado	United States	80220
3	Yale University School of Medicine - Yale Cancer Center	New Haven	Connecticut	United States	06520
4	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
5	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
6	Carolina BioOncology Institute	Huntersville	North Carolina	United States	28078
7	The Cleveland Clinic Foundation	Lyndhurst	Ohio	United States	44124
8	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
9	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
10	Virginia Cancer Specialist	Fairfax	Virginia	United States	22031