Watch and Wait in PD-1 Monoclonal Antibody Treated dMMR/MSI-H Distal Rectal Cancer

Official title

Watch and Wait in Patients With dMMR/MSI-H Distal Rectal Cancer Accessed Pathological Complete Response After PD-1 Monoclonal Antibody Therapy-an Open Label, Multicenter, Prospective Study (BASKET)

Overview

Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC) , more than fifty percent of dMMR/MSI-H CRC patients might get pathological complete response(pCR) after PD-1 monoclonal antibody treatment. For distant rectal cancer(RC), radical resection and neoadjuvant chemotherapy or chemoradiotherapy might cause lots of treatment cost,damage to defecation and sexual function, acute toxicity, chronic dysfunction, even loss of anus and psychological disorder. This study aims to evaluate the effect and safety of watch and wait in patients with dMMR/MSI-H distal RC accessed pCR after PD-1 monoclonal antibody therapy.

Detailed description

Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). MMR expression and MSS status are the important effective factors of immunotherapy. PD-1monocolnal antibody therapy has accessed excellent treatment effect in advanced dMMR/MSI-H CRC and neoadjuvant therapeutic effect in early colon cancer, more than fifty percent of dMMR/MSI-H CRC patients might get pathological complete response(pCR) after PD-1 monoclonal antibody treatment. The treatments had been proved to be safe and the toxicities were controllable. Rectal cancer(RC) is one of the most common malignant tumors in China. So far, radical resection with or without neoadjuvant chemotherapy of chemoradiotherapy are still standard comprehensive treatments recommended to distal RC by NCCN, ESMO and CSCO. For distant RC, radical resection and neoadjuvant chemotherapy or chemoradiotherapy might cause lots of treatment cost,damage to defecation and sexual function, acute toxicity, chronic dysfunction, even loss of anus and psychological disorder. So far, whether watch and wait could be performed in patients with dMMR/MSI-H distal RC accessed pCR after PD-1 monoclonal antibody therapy or not is still not clear. Thus, this study aims to evaluate the effect and safety of watch and wait in patients with dMMR/MSI-H distal RC accessed pCR after PD-1 monoclonal antibody therapy.

Interventions

• Behavioral watch and wait
  patients with DNA mismatch repair-deficient or microsatellite instability-high distal rectal cancer accessed pathological complete response after 6 courses of PD-1 monoclonal antibody (200mg/Course/Q3w) therapy and start watch and wait.

Primary outcome measures

• 1 year DFS rate [Time frame: 1 year]

Secondary outcome measures (5)

• Incidence rate of Grade ≥3 PD-1monoclonal antibody-related adverse events [Time frame: 1 year]
• local recurrent rate [Time frame: 3 years]
• distant metastasis rate [Time frame: 3 years]
• 3 years DFS Rate [Time frame: 3 years]
• 3 years OS rate [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

Preliminary inclusion criteria：

• Histological identified rectal adenocarcinoma,
• Tumor biopsy immunohistochemical (IHC) identified dMMR, including one or more deficient of the MSH1,MSH2,MSH6 and PMS2 protein expression and diagnosed as deficient mismatch repair(dMMR), or next generation sequencing identified (MSI-H)； MRI identified tumor inferior margin lower than peritoneal reflection,
• Clinical staging TxNxM0, with or without positive MRF, with or without positive EMVI,
• Staging method：all patients undergo rectal palpation, high resolution MRI ± transrectal Ultrasound examination，positive perienteric lymph node(LN): short diameter ≥10mm LN or LN with typical metastatic shape and MRI character, clinical data should be re-evaluated and judged by center evaluation group when there are contradictory stagings，distant metastasis were excluded by chest and abdominal enhanced CT and pelvic enhanced MRI,
• No intestinal obstruction symptom，or obstruction relieved after proximal colostomy,
• No rectal surgery history,
• No chemotherapy or radiotherapy history,
• No biopharmaceutical treatment history(such as monoclonal antibody), immunotherapy(such as anti PD-1antibody, anti PD-L1 antibody, anti PD-L2 antibody or anti CTLA-4), or other research drug treatment,
• Endocrinotherapy history restriction:No
• Informed consent assigned, Final inclusion criteria：
• Clinical complete response (cCR)(Chest,abdominal and pelvic enhanced CT or pelvic enhanced MRI or transrectal ultrasound proved)
• Transrectal ultrasound biopsy or endoscopic biopsy proved pathologically complete response (pCR)

Exclusion criteria

• Arrhythmia need anti-arrhythmia treatment(except β-blocking agent or Digoxin)，symptomatic coronary heart disease or myocardial ischemia(myocardial infarction within 6 months) or congestive heart-failure (CHF) > NYHA grade II,
• Severe hypertension not well controlled by drugs,
• HIV infection history or active phase of chronic Hepatitis B or C(high copies of virus DNA),
• Active tuberculosis(TB)，accepting anti-TB treatment or anti-TB treatment within 1 year before trial screen,
• Other active clinical severe infection(NCI-CTC V5.0),
• Outside pelvic distant metastasis evidences,
• Dyscrasia, organ dysfunction,
• Pelvic or abdominal radiotherapy history,
• Multiple CRC or Multi-primary tumors；
• Epilepsy need treatments(Steroid or anti-epilepsy therapy),
• Other malignant tumor history within 5 years,
• Over abuse of drugs, medical and psychological or social conditions that might interfere patients or evaluation of the study results,
• Any active autoimmune disease or autoimmune disease history (including but not restricted：interstitial pneumonia, uveitis,enteritis, hepatitis,hypophysitis, nephritis, hyperthyroidism, hypothyroidism, asthma need bronchodilators),
• Any anti-infection vaccine injection 4 weeks before inclusion ,
• Long-term exposure to immune-suppressor, combination of systemic or topical use of corticosteroids (dose>10mg/day prednisolone or equivalent hormone)；
• Known or suspicious allergy to any study related drugs,
• Any unstable state might cause damage to the safety and compliance of patients,
• Pregnant or breast feeding women who has ability to have children while without contraception,
• Refuse to sign informed consent

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

China · 1 center

• Sun Yatsen University — Guangzhou

Publications

• Scott E. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Department of Medicine; Department of Biostatistics and Computational Biology; Dana-Farber Cancer Institute, Boston; Harvard Medical Scho PMID 28159490
• Sclafani F. PD-1 inhibition in metastatic dMMR/MSI-H colorectal cancer. Lancet Oncol. 2017 Sep;18(9):1141-1142. doi: 10.1016/S1470-2045(17)30512-0. Epub 2017 Jul 19. No abstract available. PMID 28734760
• Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015 Feb 1;194(3):950-9. doi: 10.4049/jimmunol.1401686. Epub 2014 Dec 24. PMID 25539810
• Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Bl PMID 26028255
• Prasad V, Kaestner V, Mailankody S. Cancer Drugs Approved Based on Biomarkers and Not Tumor Type-FDA Approval of Pembrolizumab for Mismatch Repair-Deficient Solid Cancers. JAMA Oncol. 2018 Feb 1;4(2):157-158. doi: 10.1001/jamaoncol.2017.4182. No abstract available. PMID 29285544

Identifiers

NCT: NCT04643041 · E2020132

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗