Advanced Solid Tumor
Conditions
Brief summary
The expansion study was a Phase I, multicenter, open label feasibility trial to characterize the pharmacologic activity of IV CPX-POM in bladder tumor tissues obtained from patients with MIBC (Stage ≥T2, N0-N1, M0) who were scheduled for RC with bilateral (standard or extended) pelvic lymph node dissection (PLND). The Dose Escalation study was a Phase I, multicenter, open label, dose escalation study to evaluate the DLTs and MTD and to determine the recommended Phase 2 dose (RP2D) of CPX-POM administered IV in patients with any histologically- or cytologically-confirmed solid tumor type and was completed.
Detailed description
The expansion cohort of this study was conducted at up to 3 study sites. It was an open-label feasibility trial to characterize the pharmacologic activity of IV CPX-POM in bladder tumor tissues obtained from patients with MIBC (Stage ≥T2, N0-N1, M0) who were scheduled for RC with bilateral (standard or extended) pelvic lymph node dissection (PLND). Both cisplatin eligible and chemotherapy eligible MIBC patients scheduled for RC were eligible to participate. Neoadjuvant treatment with CPX-POM, whether alone or in combination with gemcitabine +cisplatin, started within 8 weeks of transurethral resection of the bladder tumor (TURBT) that showed muscularis propria invasion. Nine patients, four cisplatin-ineligible, and five chemotherapy-eligible patients, were enrolled. Patients who are cisplatin-ineligible were treated with two 21-day treatment cycles of CPX-POM alone (Cycle 1, Days 1-5 treatment, rest days 6-21; Cycle 2, Days 22-26 treatment, rest days 27-43) before a planned RC. Chemotherapy-eligible patients received neoadjuvant chemotherapy (gemcitabine + cisplatin in three 21-day treatment cycles) in combination with three 21-day treatment cycles of CPX-POM (Cycle 1, Days 1-5 treatment, rest days 6-21; Cycle 2, Days 22-26 treatment, rest days 27-42; Cycle 3, Days 43-47, rest days 48-63), i.e. concurrently with the prescribed chemotherapy. The cisplatin + gemcitabine dosing regimen for chemotherapy-eligible patients in the Expansion Cohort was administered per the institution's standard of care. After each infusion of CPX-POM at the RP2D of 900 mg/m2,, patients remained in the clinic for at least a 1-hour observation period. On Day 1 of Cycle 1, single blood and clean catch urine samples were collected prior to the first CPX-POM infusion. On Day 5 of Cycle 1, serial blood and complete urine samples were collected over 24 hours following the fifth, once daily CPX-POM RP2D dose of 900 mg/m2 infused over 20 minutes.
Interventions
DRUGCPX-POM
CPX-POM
Sponsors
CicloMed LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient is male or female aged ≥18 years. 2. Patient provided signed and dated informed consent prior to initiation of any study procedures. 3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry out all pre-disease activities without restriction) or 1 (unable to perform physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature). 4. Patient has a predicted life expectancy of ≥3 months. 5. Patient has a GFR of ≥30 mL/min/1.73 m\^2. 6. Patient has adequate hepatic function, as evidenced by a total bilirubin ≤1.5 × ULN, aspartate transaminase (AST), and /or alanine transaminase (ALT) ≤3 × ULN or ≤5 ×ULN, if due to liver involvement by tumor. 7. Patient has adequate bone marrow function, as evidenced by hemoglobin ≥9.0 g/dL in the absence of transfusion within the previous 72 hours, platelet count ≥100×10\^9cells/L, and absolute neutrophil count (ANC) ≥1.5×10\^9 cells/L. 8. Patient has no significant ischemic heart disease or myocardial infarction (MI) within 6 months before the first dose of CPX-POM and currently has adequate cardiac function, as evidenced by a left ventricular ejection fraction of \>50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and corrected QT interval (QTc) \<470 msec by Fridericia (QTcF). The eligibility of patients with ventricular pacemakers for whom the QT interval may not be accurately measurable will be determined on a case by-case basis by the Sponsor in consultation with the Medical Monitor. 9. Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of CPX-POM, as follows: 1. For women: Negative pregnancy test during Screening and at Day 1 of each treatment cycle and compliant with a medically approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal. 2. For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile. Men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period. 10. Patient is willing and able to participate in the study and comply with all study requirements. 11. Patients must have histologically confirmed MIBC (≥T2, N0-N1, M0 per AJCC) pure or mixed histology urothelial carcinoma. Clinical node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined to the true pelvis and are within the planned surgical LN dissection template. 12. The initial TURBT that showed muscularis propria invasion should be within 8 weeks prior to beginning study therapy, when feasible. There must be adequate evaluable tumor burden in the tissue blocks (from initial or repeat TURBT with highest tumor content) to allow for analysis as determined by the local site pathologist. 13. Patients must be ineligible for cisplatin-based chemotherapy due to any of the following: 1. Creatinine clearance(CrCl) \<60 mL/min with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 2. Hearing impaired ≥ Grade 2 by CTCAE criteria 3. Neuropathy ≥ Grade 2 by CTCAE criteria 4. Heart failure New York Heart Association (NYHA) ≥ III
Exclusion criteria
Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine Disease Response Following 2 or 3 CPX-POM Treatment Cycles by Assessing the Complete and Partial Pathologic Response Rate at the Time of Radical Cystectomy (RC) | 56 days | Tumors will be assessed in a standard manner and given grade/stage according to the American Joint Commission on Cancer (AJCC) criteria. Efficacy will be assessed based on pathologic criteria and evidence of pharmacologic activity in the target tissue. |
| Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | 56 days | Immunohistochemistry (IHC) analyses of pre-treatment (at TURBT) and post-treatment (at radical cystectomy) bladder tumor tissues were performed to determine whether neoadjuvant fosciclopirox treatment affected the Notch cell signaling pathway. Immunohistochemistry staining intensity score as a measure of protein expression with four categories: negative (0), weak (1), moderate (2), and strong (3). Staining intensity scores were assigned by a blinded pathologist who specializes in genitourinary cancers. Pre-treatment and post-treatment bladder tumor samples were available for IHC analysis for six of the nine patients studied. For two patients, pre-treatment bladder tumor tissue samples obtained from TURBT at referring sites were not processed for IHC analysis. One patient was discovered to have metastatic MIBC after enrollment, and therefore, did not undergo RC, hence, no post-treatment sample was available for IHC analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participant With Any Serious Adverse Events (SAEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) | 56 days | Incidence of Serious Adverse Events in subjects receiving CPX-POM. |
| Number of Participant With Any Adverse Events (AEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) | 56 days | Incidence of Adverse Events in subjects receiving CPX-POM. |
Countries
United States
Participant flow
Recruitment details
CPX-POM-001EXP (NCT04608045) was submitted to and approved by FDA as a protocol amendment to CPX-POM-001 (dose escalation study, NCT03348514), the Phase 1 Dose Escalation Study. The dosage regimen was determined to be the Recommended Phase 2 Dose (RP2D) defined by the CPX-POM-001 Dose Escalation Study (NCT03348514) conducted in advanced solid tumor patients. The nine patients enrolled in CPX-POM-001EXP (NCT04608045) received one dosage regimen of 900 mg/m\^2 via a 20-minute infusion.
Pre-assignment details
CPX-POM-001EXP was conducted in muscle-invasive bladder cancer (MIBC) patients scheduled for cystectomy. MIBC, cisplatin-ineligible MIBC and cisplatin-eligible MIBC patients received fosciclopirox for 2 or 3, 21-day treatment, fosciclopirox alone prior to cystectomy for 2, 21-day treatment cycles or fosciclopirox for 3, 21-day treatment cycles in combination with standard-of-care gemcitabine and cisplatin prior to cystectomy. The dosage regimen was administered in a neoadjuvant setting.
Participants by arm
| Arm | Count |
|---|---|
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion CPX-POM: CPX-POM | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion |
|---|---|
| Age, Continuous | 68.6 years STANDARD_DEVIATION 11.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Determine Disease Response Following 2 or 3 CPX-POM Treatment Cycles by Assessing the Complete and Partial Pathologic Response Rate at the Time of Radical Cystectomy (RC)
Tumors will be assessed in a standard manner and given grade/stage according to the American Joint Commission on Cancer (AJCC) criteria. Efficacy will be assessed based on pathologic criteria and evidence of pharmacologic activity in the target tissue.
Time frame: 56 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Determine Disease Response Following 2 or 3 CPX-POM Treatment Cycles by Assessing the Complete and Partial Pathologic Response Rate at the Time of Radical Cystectomy (RC) | Complete pathological response | 2 Participants |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Determine Disease Response Following 2 or 3 CPX-POM Treatment Cycles by Assessing the Complete and Partial Pathologic Response Rate at the Time of Radical Cystectomy (RC) | Pathologic downstaging | 4 Participants |
Primary
Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway.
Immunohistochemistry (IHC) analyses of pre-treatment (at TURBT) and post-treatment (at radical cystectomy) bladder tumor tissues were performed to determine whether neoadjuvant fosciclopirox treatment affected the Notch cell signaling pathway. Immunohistochemistry staining intensity score as a measure of protein expression with four categories: negative (0), weak (1), moderate (2), and strong (3). Staining intensity scores were assigned by a blinded pathologist who specializes in genitourinary cancers. Pre-treatment and post-treatment bladder tumor samples were available for IHC analysis for six of the nine patients studied. For two patients, pre-treatment bladder tumor tissue samples obtained from TURBT at referring sites were not processed for IHC analysis. One patient was discovered to have metastatic MIBC after enrollment, and therefore, did not undergo RC, hence, no post-treatment sample was available for IHC analysis.
Time frame: 56 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 2 | 1.0 score on a scale | Standard Deviation 0.9 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Nicastrin | 2.5 score on a scale | Standard Deviation 0.2 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Jagged 1 | 2.0 score on a scale | Standard Deviation 1.3 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Hes 1 | 1.5 score on a scale | Standard Deviation 1.2 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 3 | 2.5 score on a scale | Standard Deviation 1.2 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Cyclin D1 | 0.0 score on a scale | Standard Deviation 0 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Presenilin 1 | 1.3 score on a scale | Standard Deviation 1.5 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | CD8+ | 1.5 score on a scale | Standard Deviation 0.5 |
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 1 | 2.2 score on a scale | Standard Deviation 0.8 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | CD8+ | 0.5 score on a scale | Standard Deviation 0.5 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 1 | 1.3 score on a scale | Standard Deviation 1.5 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 2 | 0.2 score on a scale | Standard Deviation 0.4 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Notch 3 | 1.5 score on a scale | Standard Deviation 1.6 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Jagged 1 | 1.0 score on a scale | Standard Deviation 1.5 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Presenilin 1 | 1.0 score on a scale | Standard Deviation 1.3 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Nicastrin | 1.5 score on a scale | Standard Deviation 1.6 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Hes 1 | 0.5 score on a scale | Standard Deviation 1.2 |
| Post-treatment: CPX-POM, 900 mg/m^2 by 20-minute IV Infusion | Immunohistochemistry (IHC) Analyses of Pre-treatment (at TURBT) and Post-treatment (at Radical Cystectomy) Bladder Tumor Tissues Were Performed to Determine Whether Neoadjuvant Fosciclopirox Treatment Affected the Notch Cell Signaling Pathway. | Cyclin D1 | 0.2 score on a scale | Standard Deviation 0.4 |
Secondary
Number of Participant With Any Adverse Events (AEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
Incidence of Adverse Events in subjects receiving CPX-POM.
Time frame: 56 days
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Number of Participant With Any Adverse Events (AEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) | 9 Participants |
Secondary
Number of Participant With Any Serious Adverse Events (SAEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
Incidence of Serious Adverse Events in subjects receiving CPX-POM.
Time frame: 56 days
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CPX-POM, 900 mg/m^2 by 20 Minute IV Infusion | Number of Participant With Any Serious Adverse Events (SAEs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) | 0 Participants |