Gastrointestinal Cancer

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SU_3_2021 - Nuclear Export Inhibition for Radiosensitization; a Proof-Of-Concept Phase I Clinical Trial of Neoadjuvant KPT-330 (Selinexor) Plus Chemoradiation in Locally Advanced Rectal Cancer

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Nuclear Export Inhibition for Radiosensitization; a Proof-Of-Concept Phase I Clinical Trial of Neoadjuvant KPT-330 (Selinexor) Plus Chemoradiation in Locally Advanced Rectal Cancer
Y. Lawrence1, E. Shmueli2, N. Yarom3, M. Khaikin3, M. Venturero3, S. Apter3, Y. Inbar3, D. Aderka3, N. Halpern3, R. Berger4, A. Shani3, M. Schvimer3, S. Raskin3, A. Ackerstein3, T. Rashal3, Z. Symon1, and T. Golan1; 1Radiation Oncology, Sheba Medical Center, Ramat Gan, Israel, 2Chaim Sheba Medical Center, Department of Radiation Oncology, Ramat Gan, Israel, Ramat Gan, Israel, 3Sheba Medical Center, Ramat Gan, Israel, 4Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel

Purpose/Objective(s): Selinexor is a first-in-class exportin 1 antagonist. Exportin-1, the main nuclear export protein for tumor suppressor proteins, is upregulated in many cancer types. Ongoing phase II / III trials are testing selinexor both as a single agent and in combination with chemotherapy. Selinexor potentiates radiation-induced cell death in preclinical models, possibly through nuclear sequestration of the anti-apoptotic molecule survivin, but has yet to be combined with radiation in the clinic. Standard of care for locally advanced rectal cancer (LARC) includes neoadjuvant fluoropyrimidine-based chemoradiation (ChRT). We hypothesized that the addition of selinexor to ChRT would increase the radiological and pathological response rate to neoadjuvant treatment.

Materials/Methods: We performed a phase I “3+3” dose-escalation, single-institution clinical trial of selinexor plus ChRT for the treatment of LARC. The primary endpoints were 1) to determine safety / tolerability and 2) to determine phase II dose. Eligibility criteria included non-metastatic LARC [T3/T4 or node positive], lack of comorbidities, and good PS. Patients received 50.4 Gy over 5.5 weeks plus capecitabine 825 mg/m2 twice daily on same days as radiation. We tested 3 selinexor dose-levels and regimens: 20mg/m2 twice weekly concurrent with ChRT, 35 mg/m2 twice weekly concurrent with ChRT, and 35 mg/m2 twice weekly both concurrent with ChRT, and for an additional 2 weeks immediately following ChRT. MRI scans were performed prior to, and 4w following ChRT. Subsequently, patients underwent definitive resection.

Results: We enrolled 11 patients, median age 60.5 years (IQR 47-76.5), 5 females 6 males, stage II n=5, stage III n=6. Nine completed selinexor plus ChRT, and 2 stopped selinexor in the absence of clear toxicity. Of the 9 patients who completed treatment, 3 received selinexor at each dose level. Seven required breaks and/or dose decreases in capecitabine, and 3 required breaks and/or dose decreases in selinexor. Side effects attributed to selinexor were hyponatremia (8 Gd 1 and 1 Gd 3) and fatigue. Dose level 3 was poorly tolerated: there was one DLT (syncope), other subjects complained of fatigue, all during the post-radiation dosing period. Of the 9 patients who completed treatment, median volumetric tumor shrinkage was 93% (IQR 59-98). Comparing baseline clinical stage to final pathological stage, 7 of 9 patients were down-staged. Two patients experienced a near-complete pathological response.

Conclusion: Addition of selinexor 35mg/m2, twice-weekly to concurrent ChRT was tolerated and appeared to enhance antitumor activity. Further phase II studies are recommended.

Author Disclosure: Y. Lawrence: Research Grant; Gateway for Cancer research. Advisory Board; celgene. committee member; RTOG. E. Shmueli: None. N. Yarom: None. M. Venturero: None. D. Aderka: None. M. Schvimer: None. A. Ackerstein: None.

Yaacov Lawrence, MD, MRCP

Biography:
Dr Lawrence is a clinician scientist dedicate to furthering understanding in radiation biology and improving outcomes in cancer patients. He has authored numerous papers on combining ionizing radiation with targeted agents. More recently his lab has focused on understanding the crosstalk between the radiation response and metabolic pathways. A particular strength of Dr Lawrence is the translation of laboratory findings into the clinic, he is first author of “NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers" published in JNCI, and has led several clinical trials. Dr Lawrence is an active member of the American Society for Radiation Oncology (ASTRO), and the local PI for NRG-RTOG clinical trials. He is a previous recipient of the ASCO Young Investigator Award. Dr Lawrence has received funding from the Israel Cancer Association, European Union FP7 program, NATO, and the Rosetree’s foundation. Dr Lawrence is overall PI of an international clinical trial testing celiac plexus radiosurgery, funded by ‘Gateway for Cancer Research’.
Dr Lawrence’s clinical interests are radiation oncology as applied to the gastro-intestinal tract. He has investigated age-related-toxicity in rectal cancer (https://doi.org/10.1016/j.ijrobp.2014.05.1253), and is the PI of a recently completed Phase I clinical trial of neoadjuvant Selinexor combined with chemoradiation in rectal cancer NCT02137356 that will be presented at the ASTRO 2018 Annual meeting.

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SU_3_2021 - Nuclear Export Inhibition for Radiosensitization; a Proof-Of-Concept Phase I Clinical Trial of Neoadjuvant KPT-330 (Selinexor) Plus Chemoradiation in Locally Advanced Rectal Cancer



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