Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The expansion study is 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 will be 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
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The expansion cohort of this study will be conducted at up to 3 study sites. It will be 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 will be scheduled for RC with bilateral (standard or extended) pelvic lymph node dissection (PLND). Approximately half of the patients enrolled will be cisplatin eligible and half will be chemotherapy eligible and scheduled to receive neoadjuvant chemotherapy with gemcitabine + cisplatin. Neoadjuvant treatment with CPX-POM, whether alone or in combination with gemcitabine +cisplatin, will start within 8 weeks of transurethral resection of the bladder tumor (TURBT) that showed muscularis propria invasion. Approximately 12 patients will be enrolled. Patients who are cisplatin eligible will be treated with two 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 27-43) before a planned RC. Chemotherapy-eligible patients who are scheduled to receive neoadjuvant chemotherapy (gemcitabine + cisplatin in three 21-day treatment cycles) will be treated in addition 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 will be administered per the institution's standard of care. After each infusion of CPX-POM, patients will remain in the clinic for at least a 1-hour observation period. On Day 1 of Cycle 1, single blood and clean catch urine samples will be collected prior to the first CPX-POM infusion.

Official Title
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A Phase 1, First-in-Human, Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: CPX-POM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is male or female aged ≥18 years. Patient provided signed and dated informed consent prior to initiation of any study procedures. 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). Patient has a predicted life expectancy of ≥3 months. Patient has a GFR of ≥30 mL/min/1.73 m^2. 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. 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. 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. 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: 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. 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. Patient is willing and able to participate in the study and comply with all study requirements. 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. 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. Patients must be ineligible for cisplatin-based chemotherapy due to any of the following: Creatinine clearance(CrCl) <60 mL/min with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 Hearing impaired ≥ Grade 2 by CTCAE criteria Neuropathy ≥ Grade 2 by CTCAE criteria Heart failure New York Heart Association (NYHA) ≥ III Exclusion Criteria: Patients who meet any of the following exclusion criteria are not to be enrolled in the Expansion Cohort. Baseline GFR <30 mL/min/1.73 m^2. Women must not be pregnant or breastfeeding since we do not know the effects of CPX-POM on the fetus or breastfeeding child. Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible. Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances: Not currently active and diagnosed at least 3 years prior to the date of registration. Non-invasive diseases such as low risk cervical cancer or any cancer in situ. Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated.( (e.g. low/ intermediate risk prostate cancer, etc.). Patients may not have undergone major surgery with the exception of TURBT (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury. Patients must not have clinically significant cardiac disease. Patients may not have chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV). Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion. Patients may not have known diagnosis of any condition (e.g. post hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. Patients with any serious and/or uncontrolled concurrent medical conditions (e.g.., active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that could, in the investigator's opinion, cause unacceptable safety risks or potentially interfere with the completion of the treatment according to the protocol are not eligible. Patients may not have any live viral vaccine used for prevention of infectious diseases within 4 weeks prior to study drug(s). Patients unwilling or unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CPX-POM, 900 mg/m2 by 20 minute IV infusion<br> | Drug: CPX-POM<br>* CPX-POM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 56 days | 
| 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. | 56 days |