Camsirubicin + Pegfilgrastim to Determine MTD in ASTS
Study Details
Study Description
Brief Summary
This is an Interventional Study in Advanced Soft Tissue Sarcomas (ASTS). It is a Phase 1b, open-label, dose-escalation clinical study evaluating the safety of camsirubicin with prophylactic pegfilgrastim in the treatment of advanced soft tissue sarcomas. The objective of the study is to evaluate the safety of camsirubicin with prophylactic pegfilgrastim in the treatment of ASTS and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of camsirubicin with prophylactic pegfilgrastim. The primary endpoint is the MTD (RP2D).The secondary endpoints are: safety profile of camsirubicin with prophylactic pegfilgrastim, PFS, TTP, ORR, DoR, OS and PK. As exploratory endpoint, Quality of life will be measured by using the Functional Assessment of Cancer Therapy: General (FACT-G).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
This is a Phase 1b, open-label, dose-escalation clinical study evaluating the safety of camsirubicin with prophylactic pegfilgrastim in the treatment of advanced soft tissue sarcomas. Following a screening period of up to 28 days, eligible patients will receive camsirubicin through intravenous infusion (8 mL/min rate) on Day 1 of a 21-day cycle for 6 cycles. Dose will be based on the patient's body surface area (BSA). Patients who demonstrate clinical benefit (defined as stable disease or better) at the completion of 6 cycles will be allowed to continue to receive camsirubicin until disease progression or unacceptable toxicity or completion of their 16th cycle. All patients receiving camsirubicin will also receive 6 mg of prophylactic pegfilgrastim approximately 48-96 hours after each camsirubicin infusion to prevent neutropenia the dose escalation will start at 265 mg/m2, with dose increments of 50% until a Grade 2 non-hematologic toxicity is observed at which point subsequent dose escalations will be in increments of 25% until an MTD is identified.
At each successive dose level, cohorts of 3 new patients will be entered if no DLT is observed (3+3 design) within 21 days of initial dose. If a patient treated at any dose level experiences a DLT, a total of up to 6 patients will be treated at that dose level. Once two patients at any dose level experience a DLT, no additional patients will be treated at that level. The MTD is defined as the highest dose level below the dose level at which 2 or more patients experience a DLT during the first 21 days from Cycle 1 Day 1. This will be the RP2D unless safety concerns suggest a lower dose. Patients in each new cohort at all dose levels (i.e., all patients receiving their initial dose of camsirubicin at the designated dose level) will successfully complete one cycle of treatment prior to beginning treatment of the new cohort of patients at the next higher dose level.
The RP2D dose may be expanded by 6 patients to obtain additional PK and safety data at this dose. Patients will be followed for one year for adverse events of special interest (AESI), which includes the incidence of congestive heart failure and decreased left ventricular ejection fraction (LVEF). Patients will be followed for one year after end of treatment and AESI assessed every 3 months. Assessments will include LVEF assessment by echocardiogram or MUGA scan and measurement of Troponin-T. LVEF assessments should be collected even if the patient will go on to other anti-cancer therapies. An echocardiogram should be performed sooner if a patient develops signs and symptoms of congestive heart failure (e.g. shortness of breath during mild exertion or when lying down, feel very tired, cough (especially at night), swelling of the feet and/or ankles).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Camsirubicin + pegfilgrastim Camsirubicin phase 1b dose escalating to determine MTD |
Drug: Camsirubicin
The dose escalation of camsirubicin will start at 265 mg/m2, with dose increments of 50% until a Grade 2 non-hematologic toxicity is observed at which point subsequent dose escalations will be in increments of 25% until an MTD is identified in patients with ASTS.
|
Outcome Measures
Primary Outcome Measures
- To determine Maximum Tolerated Dose (MTD) [3 weeks after first injection]
Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) will be collected for all treated subjects at each dose level of camsirubicin to identify dose limiting toxicities (DLTs). At each successive dose level, cohorts of 3 new patients will be entered if no dose limiting toxicity (DLT) is observed (3+3 design) within 21 days of initial dose. If a patient treated at any dose level experiences a DLT, a total of up to 6 patients will be treated at that dose level. Once two patients at any dose level experience a DLT, no additional patients will be treated at that level. The MTD will be defined as the highest dose level below the dose level at which 2 or more patients experience a DLT during the first 21 days from Cycle 1 Day 1.
- Recommended Phase 2 Dose (RP2D) Camsirubicin HCl for Injection [Up to 1 year after the first dose]
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the safety expansion cohort, based on safety, tolerability, efficacy, PK, and MTD data collected during the dose escalation portion of the study.
Eligibility Criteria
Criteria
Inclusion Criteria:
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The participant must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient's routine clinical management (e.g., blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
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Age ≥18 years.
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Only locally confirmed histological diagnosis of advanced unresectable or metastatic soft tissue sarcoma (leiomyosarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor or synovial sarcoma) not amenable to curative treatment with surgery or radiotherapy.
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Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue (taken within 18 months before enrollment) must be provided for all subjects without exception for local pathology review.
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Presence of measurable disease as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
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Performance status 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale.
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The participant has not received any previous treatment with anthracyclines (not even in adjuvant therapy).
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The participant has not had any prior systemic cytotoxic therapies for advanced/metastatic sarcoma and is considered an appropriate candidate for anthracycline therapy. All previous anticancer treatments must be completed ≥21 days prior to first dose of study drug.
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Adequate hepatic, renal, cardiac, and hematologic function prior to enrollment.
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Laboratory tests must be as follows and may be repeated once at the discretion of the investigator:
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Absolute neutrophil count (ANC) ≥1,200/mm³
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Platelet count ≥100,000/mm³
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Hemoglobin >9 g/dL
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Total Bilirubin ≤1.5 mg/dL
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Prothrombin time (PT) [seconds] or international normalized ratio (INR) ≤1.5 times upper limit of normal (ULN)
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN
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Estimated creatinine clearance ≥80 mL/min (Cockcroft and Gault)
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Left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days prior to enrollment.
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Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to enrollment. A female is eligible to enter and participate in the study if she is of non-childbearing potential (i.e. physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, a bilateral oophorectomy (ovariectomy), a bilateral tubal ligation or is post-menopausal with a minimum of 1 year without menses.
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Both males and females must agree to use highly effective contraceptive precautions if conception is possible during the dosing period and up to 3 months following the last dose of study drug.
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Female patients who are lactating must agree to discontinue nursing prior to the first dose of study drug and must refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug.
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The participant has, in the opinion of the Investigator, a life expectancy of at least 3 months.
Exclusion Criteria:
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Patients who cannot tolerate pegfilgrastim.
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Known active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment.
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Prior treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or anthracenediones (including adjuvant therapy).
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Prior radiotherapy of the mediastinal/pericardial area or whole pelvis radiation. Other thoracic radiotherapy is permitted.
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The participant has symptomatic congestive heart failure (CHF), left ventricular dysfunction (LVEF <50%), severe myocardial insufficiency, cardiac arrhythmia (uncontrolled clinically significant), or cardiomyopathy.
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The participant has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction.
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The participant has a QT interval calculated using Fridericia's correction (QTcF) of
450 milliseconds (msec) for males and >470 msec for females on screening electrocardiogram (ECG).
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Females who are pregnant or breastfeeding.
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Known allergy to any of the treatment components including a history of allergic reactions attributed to compounds of chemical or biological composition similar to doxorubicin and camsirubicin (including IV lactose) or pegfilgrastim.
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The participant has a known, uncontrolled active fungal, bacterial or viral infection including human immunodeficiency virus (HIV) or viral hepatitis (B or C).
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History of another cancer with the exception of:
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adequately treated basal cell carcinoma or skin squamous cell carcinoma or
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adequately treated in situ cervical cancer or
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superficial bladder cancer or
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low risk prostate cancer or
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relapse-free interval longer than 3 years after treatment of a primary cancer with no substantial risk of recurrence.
- Conditions which would confound the assessment of the effects and/or safety of study medication in the opinion of the investigator.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sarcoma Oncology Center | Santa Monica | California | United States | 90403 |
Sponsors and Collaborators
- Monopar Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MNPR-201-001