Patient case: 78-year-old female with sarcoma; genetic feature: MDM2

Clinical trial: MGCD516 in Advanced Liposarcoma and Other Soft Tissue Sarcomas

Summary: Primary Objective:
  -  To assess the efficacy of MGCD516 in patients with advanced liposarcoma by evaluating the progression free rate at 12 weeks as compared historical controls.
  Secondary Objectives:
  -  To further evaluate the safety profile of MGCD516 by assessing adverse event rates (according to National Cancer Institute CTCAE version 4.0 criteria) in patients treated with this agent.
  -  To assess the efficacy of MGCD516 in patients with advanced liposarcoma by evaluating the overall response rate (according to RECIST 1.1 criteria), progression free survival and overall survival in patients treated with this agent.

Detailed description: Sarcomas comprise a heterogeneous group of uncommon solid tumors of mesenchymal origin, of which more than 50 subtypes have been defined. In 2015, approximately 11,930 people will be diagnosed with sarcoma, and 4,870 will die of the malignancy.
  The primary management for most localized sarcomas is surgical resection when feasible. Unfortunately, therapeutic options for patients with metastatic or unresectable disease remain limited. The various subtypes of sarcoma differ greatly in their clinical and molecular characteristics as well as response to traditional cytotoxic agents and radiotherapy. Outcomes are generally poor in advanced disease, with doxorubicin or the combination of gemcitabine and docetaxel eliciting objective responses in about 25% of patients, with median overall survival from the diagnosis of metastatic disease limited to 12 to 18 months. For the majority of patients with advanced sarcomas, outcomes remain disappointing, and new approaches are urgently needed.

Eligibility: Inclusion Criteria:
  -  Stage 1, histologically confirmed well-differentiated or de-differentiated liposarcoma. If stage 1 of the Simon II stage design fails to meet its endpoint for liposarcoma patients, an additional 16 patients will be enrolled, composed of 4 each of MPNST, synovial sarcoma, alveolar rhabdomyosarcoma and alveolar soft part sarcoma (otherwise, an additional 16 patients with well-differentiated or de-differentiated liposarcoma would be enrolled). Pathology review occurs at the center enrolling the patient on this trial.
  -  Disease must be locally advanced and unresectable or metastatic. Disease which may be resected but with an associated level of morbidity deemed unacceptable by the treating clinician is considered eligible.
  -  Patients must have measurable disease by RECIST criteria version 1.1.
  -  Patients must evidence of disease progression, either clinically or radiographically,within the 8 weeks prior to study enrollment, as determined by the principal investigator.
  -  Patients must have been treated with at least one prior systemic regimen for sarcoma. Adjuvant systemic therapy qualifies as prior therapy for the purposes of this study. There is no upper limit on previous lines of therapy received. A prior line of systemic therapy may include prior investigational agents received as part of other clinical studies.
  -  Patients must be age 18 years or older. Because no dosing or adverse event data are currently available for MGCD516 in patients less than 18 years of age, children are excluded from the present study, but will be eligible for future pediatric trials.
  -  Patients must demonstrate an ECOG performance status of 0 or 1.
  -  Patients must demonstrate normal organ and marrow function as defined below:
  -  Absolute neutrophil count (ANC) ≥ 1,500/mm3
  -  Platelet count ≥ 100,000/mm3
  -  Creatinine ≤ 1.5 times upper limit of normal OR Calculated creatinine clearance > 45 mL/min
  -  Total bilirubin ≤ 1.5 times upper limit of normal
  -  AST/ALT ≤ 1.5 times upper limit of normal
  -  Patients must demonstrate adequately controlled blood pressure at the time of study entry, as defined by a blood pressure ≤ 150/100 mmHg at study screening on at least one of two screenings conducted at least 24 hours apart. If blood pressure meets these guidelines on initial measurement, no subsequent measurement for screening is needed. Blood pressure may be assessed by automated or manual methods by an appropriately trained clinician or nurse.
  -  Patients must have normal left ventricular systolic function, as demonstrated by a transthoracic echocardiogram or MUGA scan showing a normal left ventricular ejection fraction.
  -  The effects of MGCD516 on the developing human fetus are unknown. For this reason, women of child-bearing potential and all 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 4 months after completion of MGCD516 administration. If patients do not agree to the above, they are not considered eligible.
  -  Ability to understand and willingness to sign a written informed consent document.
  Exclusion Criteria:
  -  Patients must not have received treatment with any chemotherapy, immunotherapy, radiotherapy or an investigational agent for malignancy within the 28 days preceding study registration. Patients may not have received treatment with nitrosureas or mitomycin within the 42 days prior to study registration. Patients may not have received treatment with a small molecule targeted agent (including off-label or investigational use) within 14 days preceding study registration, provided this represents at least 7 half-lives for that agent. Toxic effects from any prior therapy (except alopecia) must have resolved to grade 1 or less according to NCI CTCAE v4.0 or to the patient's baseline by the time of registration.
  -  Patients may not be receiving any other investigational agent for any purpose concurrently. Patients may not require ongoing treatment with (a) gastric pH modifying medications including proton pump inhibitors or H2 blockers (patients may switch to antacids), (b) medications which are known to be sensitive substrates or substrates with a narrow therapeutic index for the P-gp and BCRP transporters and/or (c) medications known to cause QTc prolongation with risk of Torasades. Please see Appendix 1 for a list of such prohibited concomitant medications at study entry.
  -  Patients with brain metastases which are symptomatic may not be enrolled. Those subjects with untreated brain metastases ≤ 1 cm may who are asymptomatic and for whom there are no plans for surgery, radiation or corticosteroid use may be considered eligible at the discretion of the principal investigator. Subjects with brain metastases that have been treated and are stable for at least 1 month are eligible if they are asymptomatic and not receiving corticosteroids.
  -  Patients may not have a history of allergic reaction or hypersensitivity to microcrystalline cellulose (Avicel PH302) or polysorbate 80 (Tween 80), which are components of the drug product MGCD516.
  -  Patients may not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled diabetes mellitus or uncontrolled psychiatric illness that would limit compliance with study requirements in the opinion of the principal investigator. Additionally, patients must be free of any impairment in the ability to swallow and absorb the oral study drug.
  -  Patients may not be pregnant or nursing. Pregnant women are excluded from this study because the teratogenic effects of MGCD516 have not been adequately studied. A negative pregnancy test must be documented 7 days or less prior to registration. Because there is an unknown but potential risk for adverse events to nursing infants secondary to treatment of the mother with MGCD516, breastfeeding must be discontinued prior to registration for this clinical trial.
  -  Patients may not have known HIV infection. HIV-positive patients on combination.

Relevance to patient case: not relevant