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MOLECULAR PROFILING OF ADVANCED SOFT-TISSUE SARCOMAS (MULTISARC)

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ClinicalTrials.gov Identifier: NCT03784014
Recruitment Status : Not yet recruiting
First Posted : December 21, 2018
Last Update Posted : December 21, 2018
Sponsor:
Collaborators:
Commissariat A L'energie Atomique
Institut Bergonié
Plateforme labellisée Inca – Institut Bergonié, Bordeaux
Plateforme labellisée Inca – Hôpital Européen Georges Pompidou, Paris
CIC-EC 1401/EUCLID
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary:

MULTISARC is a randomized multicenter study assessing whether high throughput molecular analysis (next generation sequencing exome - NGS) is feasible in advanced/metastatic soft-tissue sarcoma patients, that is, whether NGS can be conducted for a large proportion of patients, with results available within reasonnable delays.

In parallel, MULTISARC aims to assess efficacy of an innovative treatment strategy guided by high throughput molecular analysis (next generation sequencing exome, RNASeq [NGS]) in patients with Advanced/metastatic soft-tissue sarcomas. At the end of first-line treatment, participant's tumor profile of experimental Arm NGS (treatment strategy based on NGS results) will be discussed within a multidisciplinary tumor board which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant. Participants for whom a targetable genomic alteration has been identified will be proposed to enter in one of the subsequent phase II single-arm sub-trial.


Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: Nilotinib Drug: Ceritinib Drug: Capmatinib Drug: Lapatinib Drug: Trametinib Combination Product: Trametinib and Dabrafenib Combination Product: Olaparib and Durvalumab Drug: Palbociclib Drug: Glasdegib Drug: TAS-120 Other: Next Generation sequencing exome Phase 3

Detailed Description:

Screening phase: archival frozen tumor sample and blood sample will be used for genetic profiling. Patients can be considered as pre-eligible for the randomized phase when all genetic material have been received by the Platform.

Randomization phase: the randomization will allocate the following arms with a ratio 1:1:

  • experimental Arm NGS : treatment strategy based on NGS results [exome, RNASeq]
  • standard Arm No NGS: treatment strategy not based on NGS

Single-arm phase II sub-trial: at the end of the first-line treatment and regardless of tumor response as per RECIST v1.1, patients randomized in Arm NGS and for whom a targetable alteration has been identified by the Molecular Tumor Board will be considered as pre-eligible for the targeted sub-study. The mandatory post-chemotherapy wash-out period of 21 days will provide time to achieve all the required tests and examinations.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 960 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

MULTISARC is a randomized multicenter study assessing whether high throughput molecular analysis (next generation sequencing exome - NGS) is feasible in advanced soft tissue sarcoma participants.

In parallel, MULTISARC aims to assess efficacy of an innovative treatment strategy guided by high throughput molecular analysis, in participants with advanced soft-tissue sarcomas.

Randomization 1:1 with 1 participant randomized in experimental Arm NGS (treatment strategy based on NGS) and 1 participant randomized in standard Arm No NGS (treatment strategy not based on NGS).

At the end of first-line treatment, participant's tumor profile of experimental Arm NGS will be discussed within a multidisciplinary tumor board which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant. Participants for whom a targetable genomic alteration has been identified will be proposed to enter in one of the subsequent phase II single-arm sub-trial.

Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: MOLECULAR PROFILING OF ADVANCED SOFT-TISSUE SARCOMAS A Phase III Study
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Arm No NGS
Patients will be treated by standard first-line chemotherapy regimen and tumor assessment will be performed every 2 cycles (ie. 6 weeks) during treatment. Thereafter, disease will be managed as per standard care depending on tumor response observed at the end of the first-line treatment.
Experimental: Arm NGS

Patients will be treated by standard first-line chemotherapy regimen and tumor assessment will be performed every 2 cycles (ie. 6 weeks) during treatment. After tumor assessment at the end of first-line chemotherapy (for a maximum of 6 cycles) and regardless of tumor response as per RECIST v1.1, participants will be discussed within a multidisciplinary tumor board (molecular tumor board-MTB) which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant.

Patients for whom a targetable genomic alteration has been highlighted will be proposed to enter in a subsequent single-arm phase II sub-trials. Otherwise, thereafter, disease will be managed as per standard care depending on tumor response observed at the end of the first-line treatment

Other: Next Generation sequencing exome
Both archived tumor material and blood sample collection will be used for genetic profiling
Other Names:
  • RNA Seq
  • NGS
  • High throughput sequencing

Experimental: Arm NGS - Targeted therapy
Targeted therapy from a list of 10 targeted treatment strategies, guided by the genomic analyses: Nilotinib capsule per os 400 mg bd, continuous dosing ; Ceritinib capsule per os 450 mg od, continuous dosing; Capmatinib tablet per os 400 mg bd, continuous dosing; Lapatinib tablet per os 1500 mg od, continuous dosing; Trametinib tablet per os 2 mg od, continuous dosing; association of Trametinib tablet per os 2 mg od and Dabrafenib capsule per os 150 mg bd, continuous dosing; association of Olaparib tablet per os 300 mg bd, continuous dosing and Durvalumab intra-veinous 1500 mg on day 1, Q4W; Palbociclib capsule 125 mg od, 3 weeks on/1 week off; Glasdegib tablet per os 300 mg od, continuous dosing; TAS-120 tablet per os 20 mg od, continuous dosing.
Drug: Nilotinib
Target: KIT, PDGFRA, CSF1R Nilotinib will be administered orally, 400 mg twice daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Name: TASIGNA

Drug: Ceritinib
Target: ALK, ROS. Ceritinib will be administered orally, 450mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Name: ZYKADIA

Drug: Capmatinib
Target: MET. Capmatinib will be administered orally, 400mg twice daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.

Drug: Lapatinib
Target: ERBB2, EGFR. Lapatinib will be administered orally, 1500mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Name: TYVERB

Drug: Trametinib
Target: KRAS, NRAS, HRAS, PTPN11, NF1, MAP2K. Trametinib will be administered orally, 2 mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Name: MEKINIST

Combination Product: Trametinib and Dabrafenib

Target: KRAS, NRAS, HRAS, PTPN11, NF1, MAP2K, BRAF. Trametinib will be administered orally, 2mg once daily on a continuous basis. Dabrafenib will be administered orally, 150mg twice daily, on a continuous basis.

A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.

Other Name: MEKINIST and TAFINLAR

Combination Product: Olaparib and Durvalumab
Target: PDL1, PARP. Olaparib will be administered orally, 300mg twice daily on a continuous basis. Dabrafenib will be administered intraveinously, 1500mg on day 1 every 4 weeks. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Names:
  • LYNPARZA
  • MEDI4736

Drug: Palbociclib

Target: CDK4, CDK6. Palbociclib will be administered orally, 125mg once daily, 3 weeks on/1 week off.

A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.

Other Names:
  • IBRANCE
  • PD-0332991

Drug: Glasdegib
Target: SMO. Glasdegib will be administered orally, 300 mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.
Other Name: PF-04449913

Drug: TAS-120
Target: FGFR. TAS-120 will be administered orally, 20 mg once daily on a continuous basis. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.




Primary Outcome Measures :
  1. To assess the feasibility of high throughput molecular analysis (next generation sequencing exome [NGS] [ Time Frame: 7 weeks ]
    Feasibility will be defined as the proportion of participants for whom results from NGS are (i) interpretable and (ii) for whom a validated report of exome sequencing including a clinical recommendation from the molecular tumor board is available within 7 weeks (i.e. within at most 49 calendar days) after reception of blood and tumor samples by one of the molecular platform.


Secondary Outcome Measures :
  1. Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 1-year progression-free survival (PFS) [ Time Frame: 1 year ]
    PFS will be defined as the delay from the date of randomization to the date of progression as per RECIST v1.1 (or death, whichever occurs first

  2. Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 2-year progression-free survival (PFS) [ Time Frame: 2 years ]
    PFS will be defined as the delay from the date of randomization to the date of progression as per RECIST v1.1 (or death, whichever occurs first

  3. Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 1-year overall survival (OS) [ Time Frame: 1 year ]
    OS will be defined as the delay from the date of randomization to the date of death (whatever the cause)

  4. Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 2-year overall survival (OS) [ Time Frame: 2 years ]
    OS will be defined as the delay from the date of randomization to the date of death (whatever the cause)

  5. Assessment of the feasibility of high throughput molecular analysis in terms of delay to obtain a clinical recommendation from the molecular tumor board for patients randomized in arm NGS with interpretable NGS [ Time Frame: an average of 7 weeks ]
    Delay from the date of signature of the informed consent to the date of the molecular tumor board

  6. Assessment of the proportion of patients with Advanced STS presenting at least one targetable genomic alteration [ Time Frame: An average of 7 weeks ]
    A participant will be considered as "presenting at least one targetable genomic alteration", if the MTB considers that at least one genetic alteration identified can be matched with one of the drugs available through the MULTISARC study

  7. Assessment of the efficacy of first-line chemotherapy in terms of 1-year progression-free survival [ Time Frame: 1 year ]
    PFS will be defined as the delay from the date of onset of first-line treatment to the date of progression as per RECIST v1.1 (or death, whichever occurs first)

  8. Assessment of the efficacy of first-line chemotherapy in terms of 2-year progression-free survival [ Time Frame: 2 years ]
    PFS will be defined as the delay from the date of onset of first-line treatment to the date of progression as per RECIST v1.1 (or death, whichever occurs first)

  9. Assessment of the efficacy of first-line chemotherapy in terms of 1-year overall survival [ Time Frame: 1 year ]
    OS will be defined as the delay from the date of onset of first-line treatment to the date of death (whatever the cause).

  10. Assessment of the efficacy of first-line chemotherapy in terms of 2-year overall survival [ Time Frame: 2 years ]
    OS will be defined as the delay from the date of onset of first-line treatment to the date of death (whatever the cause).

  11. Assessment of the efficacy of first-line chemotherapy in terms of best overall response under first-line treatment [ Time Frame: Throughout the treatment period, an average of 18 weeks ]
    Best response is recorded from the date of onset of first-line treatment until the end of first-line treatment taking into account any requirement for confirmation as per RECIST v1.1 criteria

  12. Assessment of the efficacy of first-line chemotherapy in terms of 6-month objective response [ Time Frame: 6 months ]
    Objective response is defined as complete or partial response (CR, PR) as per RECIST v1.1 under first-line treatment

  13. Assessment of the efficacy of first-line chemotherapy in terms of 6-month non progression [ Time Frame: 6 months ]
    Non progression is defined as complete or partial response (CR, PR) or stable disease (SD) under first-line treatment as defined as per RECIST v1.1

  14. Assessment of the efficacy of each targeted treatment in terms of 6-month non progression [ Time Frame: 6 months ]
    Non progression is defined as complete or partial response (CR, PR) or stable disease (SD) under targeted treatment as defined as per RECIST v1.1

  15. Assessment of the efficacy of each targeted treatment in terms of 1-year progression-free survival [ Time Frame: 1 year ]
    PFS will be defined as the delay from the date of targeted treatment initiation to the date of progression as per RECIST v1.1 or death, whichever occurs first

  16. Assessment of the efficacy of each targeted treatment in terms of 1-year overall survival [ Time Frame: 1 year ]
    OS is defined as the delay from the date of targeted treatment initiation to the date of death (whatever the cause)

  17. Assessment of the efficacy of each targeted treatment in terms of best overall response under treatment [ Time Frame: Throughout the treatment period, an average of 6 months ]
    Best response (partial or complete, as per RECIST v1.1) recorded from date of targeted treatment initiation taking into account any requirement for confirmation as per RECIST v1.1 criteria

  18. Assessment of the efficacy of each targeted treatment in terms of objective response under treatment [ Time Frame: Throughout the treatment period, an average of 6 months ]
    Complete response or partial response under targeted treatment as defined as per RECIST evaluation criteria v1.1

  19. Assessment of the efficacy of each targeted treatment in terms of change in tumor size (CTS) [ Time Frame: Throughout the treatment period, an average of 6 months ]
    CTS is defined as the difference (in percentage) in tumor size burden from the date of targeted treatment initiation (baseline) to the tumor assessment

  20. Assessment of the safety profile of each targeted treatment [ Time Frame: Throughout the treatment period, an average of 6 months ]
    Safety will be assessed as per CTCAE v5

  21. Impact of the results of immunosequencing during first-line treatment [ Time Frame: At cycle 2 day 1 ]
    Correlation of TCR-sequencing data with objective response (OR)

  22. Impact of the results of immunosequencing during first-line treatment [ Time Frame: At cycle 2 day 1 ]
    Correlation of TCR-sequencing data with progression-free survival (PFS)

  23. Impact of the results of immunosequencing during first-line treatment [ Time Frame: At cycle 2 day 1 ]
    Correlation of TCR-sequencing data with overall survival (OS)

  24. Impact of the results of immunosequencing during targeted treatment [ Time Frame: At cycle 2 day 1 of targeted treatment ]
    Correlation of TCR-sequencing data with objective response (OR)

  25. Impact of the results of immunosequencing during targeted treatment [ Time Frame: At cycle 2 day 1 of targeted treatment ]
    Correlation of TCR-sequencing data with progression-free survival (PFS)

  26. Impact of the results of immunosequencing during targeted treatment [ Time Frame: At cycle 2 day 1 of targeted treatment ]
    Correlation of TCR-sequencing data with overall survival (OS)

  27. To estimate the cost-effectiveness of the strategy usdin NGS as compared to the strategy without NGS [ Time Frame: Trhoughout the study period, an average of 2 years ]
    The outcome will be the incremental cost-utility ratio or the incremental cost per incremental Quality Adjusted Life Year (QALY)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Randomized phase

Inclusion Criteria:

  • Age ≥ 18 years,
  • Histology: soft-tissue sarcoma confirmed by the RRePS Network, as recommended by the French NCI
  • Unresectable locally advanced and/or metastatic STS
  • No previous systemic treatment for advanced disease,
  • ECOG ≤ 1
  • Adequate hematological and metabolic functions: Hemoglobin > 9 g/dL and albumin > 30 g/LRandomized phase
  • Measurable disease according to RECIST 1.1.
  • Availability of suitable frozen archive tumor material from a metastatic lesion or advanced disease (not previously treated) for research purpose,
  • Archived FFPE block of specimen tumor sampling obtained anytime during disease development for research purpose,
  • Eligible to first-line standard chemotherapy regimen,
  • No prior or concurrent malignant disease diagnosed or treated in the last two years before inclusion, except for in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer,
  • Participant with a social security in compliance with the French law,
  • Voluntary signed and dated written informed consent prior to any study specific procedure (ICF1)

Exclusion Criteria:

  • Radiological evidence of symptomatic or progressive brain metastases,
  • Inability to swallow,
  • Major problem with intestinal absorption,
  • Previous allogeneic bone marrow transplant,
  • Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses, or active Hepatitis B, C and HIV or active autoimmune disease),
  • Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
  • Individuals deprived of liberty or placed under guardianship
  • Pregnant or breast feeding women,
  • Men or women refusing contraception,
  • Previous enrolment in the present study,
  • Any contraindication to first-line chemotherapy treatment.

Phase II Sub-trials

Inclusion Criteria:

  • Participants already enrolled in MULTISARC and randomized in Arm "NGS",
  • ECOG performance status < 1,
  • Measurable disease according to RECIST v1.1,
  • Molecular alteration identified by molecular profiling,
  • Participants who have received a maximum of six cycles of a first-line chemotherapy at the inclusion,
  • Participants must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement,
  • Participants will have had a minimum of 21 days gap from last chemotherapy or immunotherapy or any other pharmacological therapy and/or radiotherapy prior to the first dose of study treatment,
  • Women of childbearing potential must have a negative serum pregnancy test within 3 days of enrolment and serum/urine pregnancy test within 24 hours prior to the administration of the study drug,
  • Female with child bearing potential and male participants with partners of child bearing potential must be willing to use two effectives forms of contraception (1 highly effective method and 1 barrier method), from beginning 3 weeks before the first dose of investigational product and until 3 months after discontinuing the study.
  • Participant with a social security in compliance with the French law,
  • Voluntary signed and dated written informed consent (ICF2) prior to any study specific procedure.

Main exclusion Criteria:

  • Previous treatment with the targeted therapy,
  • No "targetable" genomic alteration generated during the screening phase either due to the lack of alteration or due to ineligible samples for genomic analysis (MULTISARC),
  • Participants with total gastrectomy,
  • Major surgery within 30 days prior to entry into the study (excluding placement of vascular access) or minor surgery within 14 days of entry into the study,
  • History of hypersensitivity to involved study drug(s) or of its excipients,
  • Radiological evidence of symptomatic or progressive brain metastases,
  • Participant with oral anticoagulation therapy,
  • Inability to swallow,
  • Major problem with intestinal absorption,
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Sponsor.
  • Previous allogeneic bone marrow transplant,
  • Altered hematopoietic or organ function,
  • Mean resting corrected QT interval (QTcF)>470msec obtained from 3 consecutive ECGs
  • Previous or current maligancies of other histologies within the last 2 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer,
  • Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses), active uncontrolled systemic bacterial, viral, or fungal infection > Grade 2 as per NCI CTCAE v5.0
  • Chronic or active hepatitis B or hepatitis C. Testing for hepatitis B surface antigen (HBs Ag) and hepatitis B core antibody (anti HBc) will be performed at screening,
  • Human immunodeficiency virus (HIV) positive,
  • Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
  • Individuals deprived of liberty or placed under guardianship,
  • Pregnant or breast feeding women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03784014


Contacts
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Contact: Helene Esperou +33 1 44 23 67 00 C16-40@inserm.fr

Locations
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France
Institut Bergonie Not yet recruiting
Bordeaux, France
Contact: Antoine ITALIANO         
Centre Jean Perrin Not yet recruiting
Clermont-Ferrand, France
Contact: Pascale DUBRAY-LONGERAS         
Centre Georges François Leclerc Not yet recruiting
Dijon, France
Contact: Nicolas ISAMBERT         
Centre Oscar Lambret Not yet recruiting
Lille, France
Contact: Nicolas PENEL         
Centre Léon Bérard Not yet recruiting
Lyon, France
Contact: Jean-Yves BLAY         
Hôpital La Timone Not yet recruiting
Marseille, France
Contact: Florence DUFFAUD         
Institut Paoli Calmettes Not yet recruiting
Marseille, France
Contact: François BERTUCCI         
Institut de Cancérologie de Montpellier Not yet recruiting
Montpellier, France
Contact: Didier CUPISSOL         
Hôpital Cochin Not yet recruiting
Paris, France
Contact: Pascaline BOUDOU-ROUQUETTE         
Hôpital Pitié Salpétrière Not yet recruiting
Paris, France
Contact: Jean-Philippe SPANO         
Institut Curie Not yet recruiting
Paris, France
Contact: Sophie PIPERNO-NEUMANN         
Centre Henri Becquerel Not yet recruiting
Rouen, France
Contact: Jean-Christophe THERY         
Institut de Cancérologie de l'Ouest - Site René Gauducheau Not yet recruiting
Saint-Herblain, France
Contact: Emmanuelle BOMPAS         
IUCT Oncopôle Not yet recruiting
Toulouse, France
Contact: Christine CHEVREAU         
Institut Gustave Roussy Not yet recruiting
Villejuif, France
Contact: Olivier MIR         
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Commissariat A L'energie Atomique
Institut Bergonié
Plateforme labellisée Inca – Institut Bergonié, Bordeaux
Plateforme labellisée Inca – Hôpital Européen Georges Pompidou, Paris
CIC-EC 1401/EUCLID
Investigators
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Principal Investigator: Antoine Italiano Institut Bergonié

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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT03784014     History of Changes
Other Study ID Numbers: C16-40
2017-002851-27 ( EudraCT Number )
First Posted: December 21, 2018    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
advanced disease
metastatic disease
Next generation sequencing exome

Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Durvalumab
Lapatinib
Olaparib
Palbociclib
Trametinib
Dabrafenib
Ceritinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors