Clinical Trials /

PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors

NCT02584647

Description:

The purpose of this study is to determine if treatment with PLX3397 and Sirolimus will be tolerated and result in shrinking of the cancer or stopping the cancer from growing. In the phase I portion, the maximum tolerate dose of the study drug will be determined. In the Phase II portion, progression free survival will be assessed at the dose level found in Phase I. Participants will continue to take the study drug until they experience an unacceptable side effect or their disease progresses. Funding Source - FDA OOPD

Related Conditions:
  • Malignant Peripheral Nerve Sheath Tumor
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: AAAO6059
  • NCT ID: NCT02584647

Conditions

  • Sarcoma
  • Malignant Peripheral Nerve Sheath Tumors

Interventions

DrugSynonymsArms
PLX3397No other namePhase 1: PLX3397 and Sirolimus
SirolimusRapamunePhase 1: PLX3397 and Sirolimus

Purpose

The purpose of this study is to determine if treatment with PLX3397 and Sirolimus will be tolerated and result in shrinking of the cancer or stopping the cancer from growing. In the phase I portion, the maximum tolerate dose of the study drug will be determined. In the Phase II portion, progression free survival will be assessed at the dose level found in Phase I. Participants will continue to take the study drug until they experience an unacceptable side effect or their disease progresses.

Detailed Description

      Malignant peripheral nerve sheath tumors (MPNSTs) represent up to 10% of adult soft tissue
      sarcomas. Due to its rarity, few MPNST-specific prospective trials exist, and treatments are
      largely based on extrapolation from results from other sarcoma subtypes. Since the molecular
      pathways driving pathogenesis within sarcoma subtypes are distinct, these treatment options
      are likely suboptimal at best. Targeted therapies that block key pathways known to drive
      MPNST will likely result in superior tumor responses with limited toxicities.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: PLX3397 and SirolimusExperimentalCohort 1 (Phase 1): Subjects with unresectable or metastatic sarcoma will take orally PLX3397 (600 - 1000mg) in combination with Sirolimus (2-6mg) daily .
  • PLX3397
  • Sirolimus
Phase 2: PLX3397 and SirolimusExperimentalCohort 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).
  • PLX3397
  • Sirolimus

Eligibility Criteria

        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

               -  ANC ≥1.5 X 10^9/L, Hgb >9 g/dL, and platelet count ≥100 X 10^9/L

               -  AST/ALT ≤ upper limit of normal (ULN) or < 2.5X ULN in the presence of liver
                  metastases, bilirubin ≤ 1.5 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 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 PLX3997. 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 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. During the study, if the use of any concomitant treatment becomes necessary
             (e.g., for treatment of an adverse event), the treatment must be recorded on the
             eCRF, including the reason for treatment, generic name of the drug, dosage, route,
             and start and stop dates of administration. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD, in milligrams) of PLX3397 in combination with Sirolimus
Time Frame:Up to 3 years
Safety Issue:
Description:For the Phase 1 cohort, the dose combination associated with a target probability of dose limiting toxicity of 0.25. The MTD will be estimated using the time to event continual reassessment method (TITE-CRM).

Secondary Outcome Measures

Measure:Overall survival rate
Time Frame:Up to 3 years
Safety Issue:
Description:The time from the start of treatment until death, estimated using the Kaplan Meier method.
Measure:Progression free survival (PFS) rate
Time Frame:Up to 3 years
Safety Issue:
Description:For the Phase 2 cohort, PFS is defined as the time from the start of treatment until disease progression or death from any cause.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gary Schwartz

Trial Keywords

  • Unresectable

Last Updated

January 9, 2017