INTERIM
Research type
Research Study
Full title
INTERIM: a randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted combination therapy In patients with BRAFV600 mutant stage 3 unresectable or metastatic Melanoma
IRAS ID
213113
Contact name
Pippa Corrie
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust
Eudract number
2016-005228-27
Duration of Study in the UK
2 years, 11 months, 29 days
Research summary
Research Summary:
Metastatic melanoma has a very poor prognosis: median overall survival is 8 months untreated and around 2 years even with optimal systemic therapies. A gene called BRAF is abnormal in about half of melanomas and biological agents targeting the BRAF pathway have been shown to extend life. They are now routinely available in NHS clinical practice.Giving BRAF and MEK inhibitor drugs together offers the best anti-cancer treatment for these patients. However, treatment is limited by side-effects (often affecting the skin) and secondary resistance (which means the cancer regrows usually after about a year).
Laboratory experiments and case reports suggest intermittent dosing of these chronic orally administered drugs makes BRAF pathway inhibitors work for longer, extending life and reducing side effects. In the INTERIM trial, we will test whether less treatment than usual is acceptable to patients and doctors and, potentially, more beneficial. We also aim to develop better tools to monitor skin side-effects.
We will recruit 150 patients with advanced BRAF mutant melanoma. All patients will receive BRAF+MEK inhibitor treatment with standard dabrafenib+tremetinib, either taken continuously every day, or with planned treatment breaks in each 28 day cycle. Comparing these 2 groups will determine if it is feasible to recruit patients and deliver intermittent therapy, any impact on patient quality of life, and an initial estimate of how long the drugs work.
Summary of Results:
A total of 86 patients were assessed for eligibility, 7 patients did not give informed consent. The remaining 79 patients were randomised (39 experimental and 40 standard arms) from 20/12/2017 to 28/02/2020 from 19 UK sites. The last patient last visit was the 27/11/2020. The recruitment rate was 0.31 per site per two months. The median patient age was 67 (ranging from 34 to 85) years old with 54.4% (43 out of 79) female.The stratification factors were well balanced between the two treatment arms. The ECOG performance status was 0 (48.1%, 38 out of 79) or 1 (40.5%, 32 out of 79) for most of the patients. Most of the patients had an AJCC stage of IVM1c (64.6%, 51 out of 79) at baseline. A total of 56 (70.9%) patients presented brain metastases, and the LDH level was ≤ ULN for 43 (54.4%) patients.
Treatment
One patient in the experimental arm did not receive any treatment during the study period. In the remaining 78 patients, patients in the two treatment arms had the same median cycle in the first 6 cycles. The total treatment duration was lower in the experimental arm with a median of 159.5 (ranging from 29 to 172) days, while the standard arm had a median treatment duration of 167.5 (ranging from 22 to 504) days in the first 6 cycles. In the whole study period, this was 259.5 (ranging from 29 to 805) and 343.0 (ranging from 22 to 993) days in the experimental and standard arm, respectively. The experimental arm received a median of 9.5 (ranging from 1 to 27) cycles, while the standard arm received a median of 10 (ranging from 1 to 34) cycles in the study period.The standard arm had a higher treatment intensity during the first 6 cycles, the median dose intensity of Dabrafenib and Trametinib was 268.8 (ranging from 65.9 to 381.8) mg/day and 2.0 (ranging from 0.9 to 5.5) mg/day, respectively. In the experimental arm, the median dose intensity of Dabrafenib and Trametinib was 231.9 (ranging from 32.6 to 361.8) mg/day and 1.1 (ranging from 0.6 to 2.6) mg/day, respectively. But more patients in the experimental arm achieved more than 80% of dose intensity. A total of 28 (73.7%) patients and 32 (84.2%) in the experimental arm achieved more than 80% of the Dabrafenib and Trametinib dose intensity, respectively. While this was 26 (65.0%) and 30 (75.0%) in the standard arm.
During the first 6 cycles, a total of 28 (73.7%) and 31 (77.5%) patients in the experimental and standard arm had a treatment interruption. About half of the patients in the experimental (18, 47.4%) and standard (22, 55.0%) arm had a dose reduction. The most common reason for patients having a treatment modification were adverse events, 60.5% (23/38) in the experimental arm and 67.5% (27/40) in the standard arm. The non-compliance rate was 26.3% (10/38) and 32.5% (13/40) in the experimental and standard arms, respectively.
Toxicity
The safety analysis was based on 78 patients. A higher percentage (92.5%, 37/40) of patients in the standard arm (vs experimental arm 86.8%, 33/38) had an AE in the study period, while the percentage (44.7%, 17/38) of patients with an SAE was higher in the experimental arm (vs standard arm 37.5%, 15/40). Grade ≥ 3 AEs were reported in 20 (52.5%) patients in the experimental arm, but in 17 (42.5%) patients in the standard arm. More patients in the standard arm (87.5% vs 76.3%) experienced AE related to the Dabrafenib or Trametinib.Efficacy
Overall Response Rate
The RECIST assessment was available for 72 patients, 37 in the experimental arm and 35 in the standard arm. The ORR was higher in the standard arm, 77.14% (27/35) in the standard arm versus 56.76% (21/37) patients in the experimental arm. But no significant difference was observed between treatment arms, the difference was 20.39% (95% CI: -0.79% to 41.56%) with a p-value of 0.069.Overall Survival
Patients had a median follow-up of 13.0 (ranging from 2.1 to 34.6) months. During which, a total of 36 patients died. The experimental arm had a median follow-up of 11.9 (ranging from 2.1 to 30.2) months with 21 (55.3%) death, while the standard arm had a median follow-up of 14.2 (ranging from 2.5 to 34.6) months with 15 (37.5%) death. The 6-month OS was 80.9% (95% CI 69.1 to 94.7%) and 87.5% (95% CI 77.8% to 98.4%) in the experimental and standard arm, respectively. No statistical difference was observed in OS between the treatment arms (log-rank test p-value = 0.1171), and the experimental arm had a hazard ratio (HR) of 1.69 (95% CI 0.87 to 3.28) compared to the standard arm.Progression Free Survival
During the follow-up period, 25 (65.8%) patients in the experimental arm and 23 (57.5%) in the standard arm had a disease progression. The 6 months PFS was 57.6% (95% CI 43.4% to 76.5%) and 76.5% (95% CI 64.2% to 91.2%) in the experimental and standard arm, respectively. No difference between the treatment arm was observed (log-rank p-value = 0.2521), and the experimental arm had a hazard ratio (HR) of 1.36 (95% CI 0.80 to 2.32) compared to the standard arm.Time to Treatment Failure
Time to treatment failure (TTF) was calculated from the date of the first treatment date until a disease progression, death, or treatment discontinuation, whichever first. Although no statistical significance (log-rank test p-value = 0.2574) was observed in TTF between treatment arms, the experimental arm had a higher treatment failure rate of 73.7% (28/38) with a median TTF of 10.7% (95% CI 7.8% to 20.5%). Whereas the standard arm had a treatment failure rate of 65.0% (26/40) with a median TTF of 7.9% (95% CI 4.8% to 12.9 %). The experimental arm had an HR of 1.36 (95% CI 0.80 to 2.32, p-value = 0.2596) compared to the standard arm.Quality of life
Two patients in the experimental arm did not complete the QoL questionnaire at baseline. The overall global health status score in the standard arm was better than baseline in the whole study period and kept increasing until month 6, except at disease progression. But the global health status kept decreasing since the beginning of the treatment. A total of 30 patients in the standard arm and 21 in the experimental arm had month 6 global health status scores available. The standard arm had a better global health status score change from baseline compared to the experimental arm at month 6, 11.97 in the standard arm and -1.27 in the experimental arm. The difference of change between treatment arms was -13.25 (95% CI -26.13 to -0.36, p-value = 0.0379).Treatment discontinuation and withdraw
A total of 26 patients in the experimental arm, and 18 patients in the standard arm had treatment discontinuation or withdrawn from the study. Among those patients, 6 patients in the experimental arm and 4 patients in the standard arm discontinued the treatment for lack of expected treatment benefit. A total of 4 patients in the experimental arm switched to continuous dosing. 5 patients in the experimental arm and 2 patients in the standard arm were discontinued due to unacceptable toxicity.REC name
East of England - Cambridge South Research Ethics Committee
REC reference
17/EE/0340
Date of REC Opinion
5 Oct 2017
REC opinion
Further Information Favourable Opinion