Sarcomas

Key Eligibility:
1. < 50 years at the time of enrollment.
2. </= 4 lung metastases, one ≥ 3 mm and all ≤ 3 cm size at diagnosis or first recurrence
3. Lung nodules considered resectable by either open thoracotomy or thoracoscopic surgery.
4. Determination of resectability is made by the institutional surgeon.
5. Exclusion: requires anatomic resection, pleural or mediastinal mets, pleural effusion, extrapulmonary disease
6. Visits: Pre-op, Day of surgery, post op, discharge, 7-14 post op 4-6 weeks post-op 3 mos. post-op

Inclusion:
--Histopathological diagnosis (fresh or banked tumor biopsy sample, collected within the last 3 years) consistent with locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection.
--At least one BICR-confirmed measurable lesion as defined by RECIST v1.1. Participants who have
received prior radiation therapy are eligible provided measurable disease falls outside of the treatment
field or within the field and has shown greater than /equal to 20% growth in size since post-treatment assessment.
-- Received 0 to 1 prior systemic treatment regimen in the advanced/metastatic setting
(adjuvant/maintenance/consolidation treatment during which metastatic disease recurrence/progression
occurred will be considered as prior systemic treatment) for chondrosarcoma.
-- Radiographic progression/recurrence of disease according to RECIST v1.1
defined as:
Radiographic progression of disease (local and/or distant) documented by 2 imaging assessments
performed no more than 6 months (±2 weeks) apart within 12 months before randomization.
OR
Any recurrence of disease (local and/or distant) after complete surgical resection and documented
by imaging within 6 months (±2 weeks) before randomization.
--Documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor
tissue available that was sourced from either a primary or metastatic tumor lesion) based on central
laboratory testing (R132C/L/G/H/S mutation variants tested).

Exclusion:
-- Prior therapy with an IDH1 inhibitor.
--Received systemic anticancer therapy <2 weeks prior to randomization (washout from prior
investigational or immune-based anticancer therapy is 4 weeks).
-- Received radiotherapy <2 weeks prior to randomization.
--Have known symptomatic brain metastases requiring steroids >10 mg per day prednisone (or
equivalent). (see protocol for more detail)
-- Major surgery within 4 weeks prior to randomization.
--Taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate
medications with a narrow therapeutic window, unless (after at least 5 half-lives have elapsed) they can
be transferred to other medications prior to randomization.
--Active Infection
-- Significant active cardiac disease within 6 months prior to randomization
-- Have LVEF <40% by ECHO scan (or by other methods according to institutional practice)
--Have a heart-rate corrected QT interval (using Fridericia’s formula) (QTcF) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Participants with a bundle branch block combined with a prolonged QTcF interval may be permitted based on local cardiology assessment.
-- Taking meds known to prolong the QT interval unless (after at least 5 half-lives have
elapsed) they can be transferred to other medications prior to randomization or unless the medications
can be properly monitored during the study. If equivalent medication is not available, QTcF should be
closely monitored
-- Known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive HIV antibody
results, or AIDS-related illness. see protocol for more detail
--Any other acute or chronic medical or psychiatric condition,
-- Known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection
or lap band, dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion
or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under
medical treatment is allowed (assuming no drug interaction potential).
--Known medical history of progressive multifocal leukoencephalopathy (PML).

1. Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of
retroperitoneal space or infra-peritoneal spaces of pelvis.
LMS _ any grade and size > 5 cm
DDLPS; MDM2 and CDK4 expression on IHC; additional proof of MDM2 amplification is highly recommended but not mandatory
Grade 3
Grade 2 with:
- FNCLCC score = 5 and clear
necrosis on imaging (whether or not
present on the biopsy).
- OR CINSARC-high (high risk
gene profile as determined by the
Complexity INdex in SARComas)
2. Unifocal tumour
3. Resectable tumour: based on pre-op imaging (CT-abdomen, potentially
also with MRI) and has to be defined by the local treating sarcoma team. Not
considered operable when the expectation is that only an R2 resection is feasible.
4. radiologically measurable disease
Exclusion:
1.Sarcoma originating from bone structure, abdominal or gynecological viscera
2. Metastatic disease
3. CHF, Angina pectoris, Acute infalmmatory heart disease, MI within 1 yr, Uncontrolled hypertenson, uncontrolled cardiac arrhythmia
4. Previous treatment with max cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones

1. Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of
retroperitoneal space or infra-peritoneal spaces of pelvis.
LMS _ any grade and size > 5 cm
DDLPS; MDM2 and CDK4 expression on IHC; additional proof of MDM2 amplification is highly recommended but not mandatory
Grade 3
Grade 2 with:
- FNCLCC score = 5 and clear
necrosis on imaging (whether or not
present on the biopsy).
- OR CINSARC-high (high risk
gene profile as determined by the
Complexity INdex in SARComas)
2. Unifocal tumour
3. Resectable tumour: based on pre-op imaging (CT-abdomen, potentially
also with MRI) and has to be defined by the local treating sarcoma team. Not
considered operable when the expectation is that only an R2 resection is feasible.
4. radiologically measurable disease
Exclusion:
1.Sarcoma originating from bone structure, abdominal or gynecological viscera
2. Metastatic disease
3. CHF, Angina pectoris, Acute infalmmatory heart disease, MI within 1 yr, Uncontrolled hypertenson, uncontrolled cardiac arrhythmia
4. Previous treatment with max cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones