Clinical trial NCT05198856: Thalidomide Combined With Chemotherapy and Monotherapy for Maintenance Treatment for Her2-negative Advanced GC
Official title: A Single-arm, Open, Prospective, Multi-center Study on Thalidomide Combined With First-line Chemotherapy and Monotherapy for Maintenance Treatment of Liver Metastases From Her2-negative Advanced Gastric Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Gastric Cancer Metastatic to Liver
Keywords: Thalidomide
maintenance treatment
gastric cancer
liver metastases
Lead sponsor: Qilu Hospital of Shandong University
Sponsor class: OTHER
First posted: 2022-01-20
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The overall incidence of liver metastases from gastric cancer is about 9.9%-18.7%. Gastric cancer has strong heterogeneity and rapid disease progression, and the prognosis of liver metastasis is poor. The 5-year survival rate of patients with liver metastases from gastric cancer is very low, making clinical treatment challenging.

Thalidomide has immunomodulatory and anti-angiogenesis effects. It has been used in the treatment of multiple myeloma for more than 20 years, and there are many clinical studies in solid tumors. In recent years, thalidomide has been found to induce the degradation of IKAROS family transcription factors IKZF1 and IKZF3 in combination with CRBN. Therefore, it is very meaningful to explore the therapeutic value of thalidomide in advanced gastric cancer liver metastasis.

Detailed description: The overall incidence of liver metastases from gastric cancer is about 9.9%-18.7%. Gastric cancer has strong heterogeneity and rapid disease progression, and the prognosis of liver metastasis is poor. The 5-year survival rate of patients with liver metastases from gastric cancer is very low, making clinical treatment challenging. Although immune checkpoint inhibitors have been approved for third-line treatment of advanced gastric cancer, they are expensive and poorly accessible. For patients with poor economic conditions, combination therapy based on chemotherapy regimen or treatment regimen optimization may still be a relatively important direction.

Thalidomide has immunomodulatory and anti-angiogenesis effects. It has been used in the treatment of multiple myeloma for more than 20 years, and there are many clinical studies in solid tumors. In recent years, thalidomide has been found to induce the degradation of IKAROS family transcription factors IKZF1 and IKZF3 in combination with CRBN.

In addition, the sedative effect of thalidomide helps to improve patients' sleep. Thalidomide can also inhibit inflammatory factors such as TNF-α, thus improving appetite and increasing lean body weight in patients with cachexia. Its antiemetic effects can reduce gastrointestinal reactions to chemotherapeutic drugs in combined therapy. Thalidomide is also very cheap in China, which is suitable for patients on long-term maintenance treatment. Therefore, it is of great significance to explore the therapeutic value of thalidomide in liver metastasis of advanced gastric cancer.

Eligibility criteria: Inclusion Criteria:

1. Aged 18-75 years old;
2. ECOG physical status score 0-1 points (within 3 days before starting treatment);
3. Expected survival period ≥ 3 months;
4. Basically normal functions of major organs;
5. Pathologically confirmed metastatic gastric cancer or adenocarcinoma at the gastroesophageal junction with no chance of radical surgery, accompanied by liver metastasis or simple liver metastasis;
6. No previous medical treatment; If neoadjuvant or adjuvant chemotherapy has been performed before and after surgery, recurrence can be defined as first-line therapy only after drug withdrawal for at least six months;
7. HER2 negative. HER2 negative definition: IHC (0 or 1+), or IHC (2+) but negative for FISH (HER2:CEP17\<2 with mean HER2 copy number \<4.0 signals/cell);
8. Measurable lesions assessed according to RECIST1.1;
9. Able to swallow pills normally.

Exclusion Criteria:

1. Those who are allergic to thalidomide;
2. Pregnant or lactating women;
3. Severe mental illness;
4. Those who cannot take medication or follow up as planned;
5. During the trial period and within 3 months after the trial, the subjects and their partners are not willing to use contraception;
6. Participants in other clinical studies 3 months prior to the trial；
7. Patients who are financially well off and willing to use immune checkpoint inhibitors.

Primary outcomes:
measure: progression-free survival (PFS)
timeFrame: Randomization to the first occurrence of disease progression or death from any cause up to the clinical cut off date of March10,2024 (up to approximately 18 months) ]
Secondary outcomes:
measure: Quality of life (QOL)
timeFrame: UpUp to end of study (up to approximately 24 months)
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Up to end of study (up to approximately 24 months)
Other outcomes:
Locations:
Study officials:
References:
citation: Riihimaki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. Metastatic spread in patients with gastric cancer. Oncotarget. 2016 Aug 9;7(32):52307-52316. doi: 10.18632/oncotarget.10740.
citation: Cheon SH, Rha SY, Jeung HC, Im CK, Kim SH, Kim HR, Ahn JB, Roh JK, Noh SH, Chung HC. Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases. Ann Oncol. 2008 Jun;19(6):1146-53. doi: 10.1093/annonc/mdn026. Epub 2008 Feb 27.
citation: Xiao Y, Zhang B, Wu Y. Prognostic analysis and liver metastases relevant factors after gastric and hepatic surgical treatment in gastric cancer patients with metachronous liver metastases: a population-based study. Ir J Med Sci. 2019 May;188(2):415-424. doi: 10.1007/s11845-018-1864-4. Epub 2018 Jul 30.
citation: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6.
citation: Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 May 10;4(5):e180013. doi: 10.1001/jamaoncol.2018.0013. Epub 2018 May 10.
citation: Zhou S, Wang F, Hsieh TC, Wu JM, Wu E. Thalidomide-a notorious sedative to a wonder anticancer drug. Curr Med Chem. 2013;20(33):4102-8. doi: 10.2174/09298673113209990198.
citation: Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004 Apr;4(4):314-22. doi: 10.1038/nrc1323. No abstract available.
citation: Stewart AK. Medicine. How thalidomide works against cancer. Science. 2014 Jan 17;343(6168):256-7. doi: 10.1126/science.1249543.
citation: Mantovani G, Maccio A, Madeddu C, Serpe R, Massa E, Dessi M, Panzone F, Contu P. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist. 2010;15(2):200-11. doi: 10.1634/theoncologist.2009-0153. Epub 2010 Feb 15.