- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02584647
PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors (PLX3397)
Phase I Study Evaluating Combination Therapy With the Receptor Tyrosine Kinase Inhibitor PLX3397 and Sirolimus in Patients With Unresectable Sarcoma and Phase II Study in Malignant Peripheral Nerve Sheath Tumors
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Iowa
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Iowa City, Iowa, United States, 52242
- University of Iowa
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Early Drug Development Center
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Michigan
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Ann Arbor, Michigan, United States, 48109-5848
- University of Michigan
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Missouri
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Saint Louis, Missouri, United States, 63110
- Washington University in St. Louis
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New York
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New York, New York, United States, 10032
- Columbia University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Disease site/type with pathologic confirmation of diagnosis at participating cancer site.
- Phase 1: Advanced, unresectable sarcoma (any subtype)
- Phase 2: Advanced, unresectable malignant peripheral nerve sheath tumors (MPNSTs)
- Extent of disease: Unresectable
Allowable prior therapy
- Phase 1: Progressed on standard of care therapy with up to three prior treatments
- Phase 2: MPNST with 0-3 prior systemic treatments (no prior radiotherapy is necessary).
- Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2
- Age greater or equal to 18 years. Because no dosing or adverse event data are currently available on the use of PLX3397 in combination with sirolimus in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
- Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Allowable laboratory values with date range
- Absolute neutrophil count (ANC) ≥1.5 x 10^9/L, hemoglobin (Hgb) >9 g/dL, and platelet count ≥100 X 10^9/L
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ upper limit of normal (ULN) or < 2.5 x ULN in the presence of liver metastases, bilirubin ≤ 1.5 x ULN, albumin ≥ 3.0g/dL.
- Bilirubin ≤ ULN; patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the principal investigator.
- Albumin ≥ 3.0g/dL.
- Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) > 60 mL/min using the Cockcroft-Gault formula less than eight days pior to start of treatment.
- Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use an effective form of contraception from the time of the negative pregnancy test and for a minimum of 3 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive (injectable or implantable) in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential must have been postmenopausal for ≥ 1 year or surgically sterile. The effects of PLX3397 and sirolimus on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of PLX3397 and sirolimus administration.
- Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of study drug.
- Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
- Agree to pre and post-treatment tumor biopsies.
- Prior treatment-related Adverse Events must be ≤ grade 1 (CTCAE v4.0), except alopecia, at time of initiating study drug.
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier or within 14 days from cycle 1 day 1 of PLX3397 and sirolimus.
- Patients who are receiving any other investigational agents concurrently.
- Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).
- Patients with symptomatic brain metastases. Subjects with untreated brain metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor and do not require immediate radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids or if they do not require steroids following successful local therapy.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to PLX3397 or sirolimus.
- For Phase 2 - Prior exposure to a receptor tyrosine kinase or mammalian target of Rapamycin inhibitor.
- Pregnant women are excluded from this study because PLX3397 and sirolimus are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PLX3397 and sirolimus, breastfeeding should be discontinued if the mother is treated with PLX3397 and sirolimus.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active liver disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Sponsor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible.
- Major surgical procedure or significant traumatic injury within 14 days of initiating study drug or anticipation of the need for major surgery during the study.
- Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy within 28 days prior to study entry.
- Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an external biliary shunt, or significant bowel resection that would preclude adequate absorption.
- Congestive heart failure (CHF) New York (NY) Heart Association class III or IV; unstable coronary artery disease (myocardial infarction (MI) more than 6 months prior to study entry is permitted); or serious cardiac arrhythmia.
- Baseline QTc corrected by Fridericia's formula (QTcF) ≥ 450 ms (males) or ≥ 470 ms (females)
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PLX3397. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Similarly, patients with chronic or acute hepatitis C virus (HCV) or hepatitis B virus (HBV) infection are also ineligible.
- Of the five major cytochrome P450 (CYP) isoforms, 3A4 (BFC) may be involved in Phase I metabolism of PLX3397, with possibly CYP1A2 playing a minor role. Until information regarding exposure toxicity and exposure-response relationships are available with PLX3397, concomitant strong CYP3A4 inhibitors and inducers are not permitted in the event they alter the systemic exposure to PLX3397 (see Attachment 1 for a list of common CYP3A4 inhibitors and inducers). These include anticonvulsants, mycin antimicrobials, and antiretrovirals. Some common examples include inhibitors such as erythromycin, fluoxetine, gemfibrozil, and inducers such as rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine. Concomitant treatment is permitted if the medication is not expected to interfere with the evaluation of safety or efficacy of the study drug. Sirolimus undergoes extensive hepatic and intestinal metabolism via CYP3A4 and CYP3A5, as well as excretion by P-glycoprotein. Strong CYP3A inhibitors such as ketoconazole or grapefruit juice are not permitted. Patients should be monitored for supratherapeutic toxic levels of sirolimus and PLX3397. As bone marrow suppression including anemia, neutropenia, and thrombocytopenia have been reported in patients receiving sirolimus monotherapy, these adverse effects may be exacerbated in combination with PLX3397 for which patients will be closely monitored.
- Any patients on warfarin therapy
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Phase 1: PLX3397 and Sirolimus
Cohort 1 (Phase 1): Subjects with unresectable or metastatic sarcoma will take orally PLX3397 (600 - 1000mg) in combination with Sirolimus (2-6mg) daily .
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PLX3397 is a small molecule that potently and selectively inhibits macrophage colony-stimulating factor receptor (FMS), Kit, and FMS-like tyrosine kinase 3 (Flt3)-internal tandem duplication (ITD) kinases, which regulate key components of the tumor microenvironment and oncogenic variants of these kinases that drive certain tumors.
Other Names:
Sirolimus is a macrocyclic lactone that binds to tacrolimus (FK506) binding protein 12 and inhibits mammalian target of rapamycin (mTOR) resulting in cell-cycle arrest and apoptosis. Sirolimus is currently approved as an immunosuppressive agent for organ transplantation and more recently, as a component of cardiac arterial stents because of its potent antiproliferative effects on fibroblasts responsible for restenosis after such a procedure (26) Sirolimus is commonly administered orally on a daily basis, in doses ranging from 2 to 40 mg/day.
Other Names:
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Experimental: Phase 2: PLX3397 and Sirolimus
Cohort 2 (Phase 2): Subjects with unresectable or metastatic Malignant Peripheral Nerve Sheath Tumors (MPNSTs) will take PLX3397 and Sirolimus at the recommended Phase 2 dose (RP2D).
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PLX3397 is a small molecule that potently and selectively inhibits macrophage colony-stimulating factor receptor (FMS), Kit, and FMS-like tyrosine kinase 3 (Flt3)-internal tandem duplication (ITD) kinases, which regulate key components of the tumor microenvironment and oncogenic variants of these kinases that drive certain tumors.
Other Names:
Sirolimus is a macrocyclic lactone that binds to tacrolimus (FK506) binding protein 12 and inhibits mammalian target of rapamycin (mTOR) resulting in cell-cycle arrest and apoptosis. Sirolimus is currently approved as an immunosuppressive agent for organ transplantation and more recently, as a component of cardiac arterial stents because of its potent antiproliferative effects on fibroblasts responsible for restenosis after such a procedure (26) Sirolimus is commonly administered orally on a daily basis, in doses ranging from 2 to 40 mg/day.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum tolerated dose (MTD) - Phase 1
Time Frame: Up to 3 years
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The highest dose of a drug or treatment that does not cause unacceptable side effects, which will be used in Phase 2.
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Up to 3 years
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Progression free survival (PFS) rate - Phase 2
Time Frame: Up to 3 years
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The time from the start of treatment until disease progression or death from any cause, calculated in years.
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Up to 3 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Overall survival rate
Time Frame: Up to 3 years
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The time from the start of treatment until death, estimated using the Kaplan Meier method, calculated in years.
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Up to 3 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Gulam A. Manji, MD, Columbia University
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Neuromuscular Diseases
- Neoplasms, Nerve Tissue
- Peripheral Nervous System Diseases
- Nervous System Neoplasms
- Neoplasms, Connective Tissue
- Peripheral Nervous System Neoplasms
- Neoplasms, Fibrous Tissue
- Fibrosarcoma
- Neurofibroma
- Sarcoma
- Nerve Sheath Neoplasms
- Neurofibrosarcoma
- Physiological Effects of Drugs
- Anti-Infective Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Sirolimus
Other Study ID Numbers
- AAAO6059
- R01FD005745 (U.S. FDA Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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