Dataset Information

Phase II-Studie: Standardchemotherapie Capecitabin in Kombination mit Bevacizumab in der Erstlinientherapie beim metastasierten kolorektalen Karzinom

ABSTRACT: Primary objectives: Progressionsfreie Rate (PFS-Rate) nach 9 Monaten, definiert ab Tag des Therapiebeginns bis zum ersten Auftreten irgendeines der folgenden Ereignisse: Diagnose einer Progression der Erkrankung, eines Zweitmalignoms oder Tod jedweder Ursache Primary endpoints: Es handelt sich um eine Phase II-Studie, mit der die Effektivität einer innovativen Chemo/Immuntherapie-Kombination, bestehend aus Capecitabin und Bevacizumab im Hinblick auf eine zukünftige Erprobung im Rahmen einer umfangreichen Phase III-Studie abgeschätzt werden soll. Als primäres Zielkriterium dient hierbei die progressionsfreie Rate (PFS-Rate) nach 9 Monaten. Diesem Endpunkt wird der Vorzug gegenüber der objektiven Remissionsrate gegeben, da die bisherigen Erfahrungen mit den neuen Wirkstoffen dafür sprechen, dass ihr Potential sich in stärkerem Maße bei der Verzögerung einer Progression bzw. sogar Überlebensverlängerung auswirkt als bei der kurzfristigen Induktion deutlicher Tumorrückbildungen.

DISEASE(S): Metastasized Colorectal Cancer

PROVIDER: 2517518 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

Dataset Information

Phase II-Studie: Standardchemotherapie Capecitabin in Kombination mit Bevacizumab in der Erstlinientherapie beim metastasierten kolorektalen Karzinom

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