Selinexor Plus Gemcitabine in Selected Advanced Soft-tissue Sarcoma and Osteosarcoma

NCT ID: NCT04595994

Last Updated: 2024-01-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-02
• Study Completion Date: 2026-05-31

Brief Summary

Phase I-II, randomized, open-label, multicenter, international clinical trial Patients with advanced soft-tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, alveolar soft-part sarcoma) and osteosarcoma will receive selinexor in combination with gemcitabine.

Detailed Description

Phase I-II, randomized, open-label, multicenter, international clinical trial Patients with advanced soft-tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, alveolar soft-part sarcoma) and osteosarcoma will receive selinexor in combination with gemcitabine.

In the Phase I part safety and toxicity of the combination will be assessed using a 3+3 design. The recommended dose for the Phase II will be determined.

In the Phase II part there will be 4 different cohorts:

Cohort 1: Undifferentiated pleomorphic sarcoma (UPS) Cohort 2: Leiomyosarcoma (LMS) Cohort 3: Alveolar soft-part sarcoma (ASPS) Cohort 4: Osteosarcoma Patients will be randomized for phase II part only (except in cohort 3) in an open-label way to receive selinexor in combination with gemcitabine versus gemcitabine alone

Conditions

Sarcoma,Soft Tissue

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Selinexor + Gemcitabine

Dose escalation levels (Phase I):

All included patients will take both drugs:

Selinexor weekly (given on days 1,8 and 15 of each cycle) will be dispensed at different dose levels: dose level 1:60 mg, dose level 2: 60 mg, dose level 3: 60 mg, and dose level 4: 80 mg).

Gemcitabine weekly (given on days 1, 8 of each cycle) will be administered at different dose levels: (dose level 1:1000 mg/m2 (30 min), dose level 2:1000 mg/m2 (10 mg/m2/min), dose level 3:1200 mg/m2 (10 mg/m2/min) and dose level 4: 1200 mg/m2 (10 mg/m2/min)).

Selinexor: tablet (20 mg tablets) Oral use.

Gemcitabine: Concentrate for solution for infusion. Intravenous use.

Group Type: EXPERIMENTAL

Selinexor

Intervention Type: DRUG

For both interventional ( Selinexor and Gencitabine) Dose-limiting toxicity (DLT) will be applied only to either of the following toxicities occurring during the first treatment cycle (days 1-21).

Interventions

Selinexor

For both interventional ( Selinexor and Gencitabine) Dose-limiting toxicity (DLT) will be applied only to either of the following toxicities occurring during the first treatment cycle (days 1-21).

Intervention Type: DRUG

Other Intervention Names

Gemcitabine

Eligibility Criteria

Inclusion Criteria

1. Patients must provide written informed consent prior to performance of any study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient's routine clinical management (e.g. imaging tests), obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.

2. Age: 18-80 years

3. Histologic diagnosis of soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, alveolar soft part sarcoma) or osteosarcoma confirmed by central pathology review prior to enrolment with an archive tumor sample. A fresh paraffin embedded tumor tissue block must be provided for all subjects for biomarker analysis before and (when feasible) after treatment with investigational products.

4. Metastatic/advanced disease in progression in the last 6 months.

5. Patients have previously received at least one previous line of systemic therapy

6. Measurable disease according to RECIST 1.1 criteria.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

8. Adequate hepatic, renal, cardiac, and hematologic function.

9. Laboratory tests as follows:

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine ≤ 1.5 mg/dL

10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.

11. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to enrollment and agree to use birth control measures during study treatment and for 3 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

Exclusion Criteria

1. Three or more previous lines of chemotherapy

2. Prior selinexor or another XPO1 inhibitor treatment.

3. Administration of a previous gemcitabine-containing treatment.

4. Any concurrent medical condition or disease (e.g. uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.

5. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.

6. Pregnant or breastfeeding females.

7. Body surface area (BSA) <1.4 m2 at baseline, calculated by the Du Bois(31) or osteller(32) method.

8. Life expectancy of less than 3 months.

9. Major surgery within 4 weeks prior to C1D1.

10. Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or dysfunction that could interfere with absorption of study treatment.

11. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and anorexia/cachexia (palliative care).

12. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.

13. Presence of brain or central nervous system metastases, unless they are controlled (patients with treated and stable metastasis are eligible).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Grupo Espanol de Investigacion en Sarcomas

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Javier Martín Broto, MD

Role: STUDY_DIRECTOR

Hospital Fundación Jiménez Díaz

Locations

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Site Status: ACTIVE_NOT_RECRUITING

HU Vall d'Hebron

Barcelona, , Spain

Site Status: RECRUITING

H. Fundación Jiménez Díaz

Madrid, , Spain

Site Status: RECRUITING

Hospital Clínico San Carlos

Madrid, , Spain

Site Status: RECRUITING

Hospital Universitario La Paz

Madrid, , Spain

Site Status: RECRUITING

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Site Status: RECRUITING

Countries

Spain

Central Contacts

Patricio Ledesma

Role: CONTACT

ensayos@sofpromed.com

971 439 900 ext. +34

Gabriel Joan Viver Llompart

Role: CONTACT

gviver@sofpromed.com

971 439 900 ext. +34

Facility Contacts

Claudia Valverde, MD

Role: primary

cmvalver@vhebron.net

Javier Martín Broto, MD

Role: primary

jmartin@atbsarc.org

Antonio Casado, MD

Role: primary

antoniocasado6@gmail.com

Andrés Redondo, MD

Role: primary

aredondo12@gmail.com

Javier Martínez Trufero, MD

Role: primary

Role: backup

jmtrufero@seom.org

References

Kashyap T, Argueta C, Unger T, Klebanov B, Debler S, Senapedis W, Crochiere ML, Lee MS, Kauffman M, Shacham S, Landesman Y. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents. Oncotarget. 2018 Jul 20;9(56):30773-30786. doi: 10.18632/oncotarget.25637. eCollection 2018 Jul 20.

Reference Type: BACKGROUND

PMID: 30112106 (View on PubMed)

Park KS, Han BG, Lee KH, Kim DS, Kim JM, Jeon H, Kim HS, Suh SW, Lee EH, Kim SY, Lee BI. Depletion of nucleophosmin via transglutaminase 2 cross-linking increases drug resistance in cancer cells. Cancer Lett. 2009 Feb 18;274(2):201-7. doi: 10.1016/j.canlet.2008.09.007. Epub 2008 Oct 11.

Reference Type: BACKGROUND

PMID: 18851895 (View on PubMed)

Hill R, Rabb M, Madureira PA, Clements D, Gujar SA, Waisman DM, Giacomantonio CA, Lee PW. Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy. Cell Death Dis. 2013 Sep 5;4(9):e791. doi: 10.1038/cddis.2013.307.

Reference Type: BACKGROUND

PMID: 24008735 (View on PubMed)

Other Identifiers

2019-000652-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GEIS-67

Identifier Type: -

Identifier Source: org_study_id