Selinexor Plus Gemcitabine in Selected Advanced Soft-tissue Sarcoma (SeliSarc)

Official title

Phase I/II Randomized Clinical Trial of Selinexor Plus Gemcitabine in Selected Advanced Soft-tissue Sarcomas

Overview

Phase I-II, non-randomized, single-arm, open-label, multicenter, international clinical trial. Patients with advanced soft-tissue sarcoma (leiomyosarcoma or malignant peripheral nerve sheath tumor) will receive selinexor in combination with gemcitabine.

Detailed description

Phase I-II, non-randomized, single-arm, open-label, multicenter, international clinical trial.

Patients with advanced soft-tissue sarcoma (leiomyosarcoma or malignant peripheral nerve sheath tumor) 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 2 different cohorts:

Cohort 1: Leiomyosarcoma (LMS) Cohort 2: Malignant peripheral nerve sheath tumor (MPNST)

Interventions

• Drug Selinexor 20 MG
  After having completed the Phase I part, the recommended dose for Phase II is 60mg Selinexor
• Drug Gemcitabine
  Gemcitabine will be given at the dose 1200 mg/m2 (10 mg/m2/min) days 1 and 8 every 21 days.

Primary outcome measures

• progression-free survival rate (PFSR) [Time frame: 6 months]

Secondary outcome measures (5)

• Overall survival (OS) [Time frame: 6 months]
• Overall response rate (ORR) according to RECIST 1.1 [Time frame: 6 months]
• Evaluate the efficacy according to Choi response [Time frame: 6 months]
• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [Time frame: 6 months]
• Patients's quality of life (QoL) [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• 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.
• Age: 18-80 years.
• Histologic diagnosis of soft tissue sarcoma (leiomyosarcoma or malignant peripheral nerve sheath tumor) 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.
• Metastatic/advanced disease in progression in the last 6 months.
• Patients have previously received at least one previous line of systemic therapy.
• Measurable disease according to RECIST 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Adequate hepatic, renal, cardiac, and hematologic function.
• 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

• Three or more systemic treatment lines (including both chemotherapy and targeted therapy) for advanced disease (localized unresectable or metastatic).
• Patients who have received any other anti-cancer therapy or investigational product in the last 21 days prior to enrollment.
• Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer, adequately treated cervical carcinoma in situ, superficial bladder carcinoma) during the 5 years prior to randomization. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.
• Prior selinexor or another XPO1 inhibitor treatment.
• Administration of a previous gemcitabine-containing treatment.
• 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.
• 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.
• Pregnant or breastfeeding females.
• Body surface area (BSA) <1.4 m2 at baseline, calculated by the Du Bois(25) or Mosteller(26) method.
• Life expectancy of less than 3 months.
• Major surgery within 4 weeks prior to C1D1.
• Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or dysfunction that could interfere with absorption of study treatment.
• 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).
• 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. 15. Presence of brain or central nervous system metastases, unless they are controlled (patients with treated and stable metastasis are eligible)
• Presence of brain or central nervous system metastases, unless they are controlled (patients with treated and stable metastasis are eligible)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 11 centers

• Hospital Universitario de Canarias — Santa Cruz de Tenerife
• Hospital de la Santa Creu i Sant Pau — Barcelona
• Hospital Universitario Vall d'Hebron — Barcelona
• Hospital Universitario de Donostia — Donostia / San Sebastian
• Hospital General Universitario Gregorio Marañón — Madrid
• Hospital Clínico San Carlos — Madrid
• Hospital Universitario Fundación Jiménez Díaz — Madrid
• Hospital Universitario La Paz — Madrid
• … and 3 more centers

Publications

• Turner JG, Sullivan DM. CRM1-mediated nuclear export of proteins and drug resistance in cancer. Curr Med Chem. 2008;15(26):2648-55. doi: 10.2174/092986708786242859. PMID 18991627
• Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015 Mar 1;4:7. doi: 10.1186/s40164-015-0002-5. eCollection 2015. PMID 25745591
• Yao Y, Dong Y, Lin F, Zhao H, Shen Z, Chen P, Sun YJ, Tang LN, Zheng SE. The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep. 2009 Jan;21(1):229-35. PMID 19082467
• Gravina GL, Senapedis W, McCauley D, Baloglu E, Shacham S, Festuccia C. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014 Dec 5;7:85. doi: 10.1186/s13045-014-0085-1. PMID 25476752
• Abdul Razak AR, Mau-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, Saint-Martin JR, Carlson R, Landesman Y, McCauley D, Rashal T, Lassen U, Kim R, Stayner LA, Mirza MR, Kauffman M, Shacham S, Mahipal A. First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. J Clin Oncol. 2016 Dec;34(34):4142-4150. d PMID 26926685
• Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, Keohan ML, Loong HH, D'Angelo SP, Baker S, Condy M, Nyquist-Schultz K, Tanner L, Erinjeri JP, Jasmine FH, Friedlander S, Carlson R, Unger TJ, Saint-Martin JR, Rashal T, Ellis J, Kauffman M, Shacham S, Schwartz GK, Abdul Razak AR. Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory PMID 27458288
• Gounder MM, Razak AA, Somaiah N, Chawla S, Martin-Broto J, Grignani G, Schuetze SM, Vincenzi B, Wagner AJ, Chmielowski B, Jones RL, Riedel RF, Stacchiotti S, Loggers ET, Ganjoo KN, Le Cesne A, Italiano A, Garcia Del Muro X, Burgess M, Piperno-Neumann S, Ryan C, Mulcahy MF, Forscher C, Penel N, Okuno S, Elias A, Hartner L, Philip T, Alcindor T, Kasper B, Reichardt P, Lapeire L, Blay JY, Chevreau C, PMID 35394800
• Ishizawa J, Kojima K, Hail N Jr, Tabe Y, Andreeff M. Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. Pharmacol Ther. 2015 Sep;153:25-35. doi: 10.1016/j.pharmthera.2015.06.001. Epub 2015 Jun 3. PMID 26048327

Identifiers

NCT: NCT06114004 · SELNET-7-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗