Uni-Koeln-3140

University of Cologne

Albertus-Magnus-Platz , Cologne, Germany, 50923

German Hodgkin Study Group (GHSG), Trial Coordination Center, +49 22147888200, ghsg@uk-koeln.de

German Hodgkin Study Group (GHSG), Trial Coordination Center, +49 22147888200, ghsg@uk-koeln.de

No

No

No

Final

01 Nov 2024

No

Yes

04 May 2024

Yes

The primary aim of this international, prospective, multicenter phase II proof-of-concept trial is to demonstrate the efficacy of the experimental treatment strategy. The combination of immune checkpoint inhibition with nivolumab and immunogenic radiotherapy is expected to act synergistically, offering a well-tolerated and effective therapeutic approach in patients with relapsed or refractory Hodgkin lymphoma previously treted with an anti-pD1 antibody. The study is specifically designed to assess the abscopal effect of localized radiotherapy directed at a single lesion.

Participants give their written informed consent to participate in the trial. They may discontinue trial treatment at any time at their own request. Protocol treatment must be stopped in the event of pregnancy in a female participant, unless re-consent for continuation is obtained. Treatment may also be terminated at the discretion of the treating physician in cases of unacceptable toxicity, disease progression (PD), or serious comorbid conditions. Early termination of the entire trial may be initiated by the trial chairman if: - the formal stopping criterion regarding the primary endpoint is met, - participant safety is at risk, - the risk-benefit ratio for patients changes significantly, - the trial medication can no longer be justifiably used, - the sponsor (represented by the trial chairman) deems discontinuation necessary for safety reasons, - the trial proves unfeasible due to low recruitment or major shifts in the treatment landscape or sequencing for relapsed/refractory Hodgkin lymphoma (rrHL). An independent Data Monitoring Committee (DMC) oversees trial progress and patient safety. The GHSG Trial Coordination Center ensures that the DMC receives all necessary information. Regular safety analyses are conducted for all patients (FAS) to monitor: - Study eligibility, - Disease progression, relapse, and mortality during and after treatment, - Adverse events (AEs) and serious adverse events (SAEs). - Cases of early treatment discontinuation are documented and analyzed for safety assessment and to identify patients who may need to be replaced in the Abscopal Response Analysis Set (ARAS).

05 Dec 2019

Yes

Yes

Netherlands: 4

Norway: 2

Austria: 5

Germany: 15

26

26

0

0

0

0

0

0

20

5

1

Stage-2 (overall period)

Non-randomised - controlled

Nivolumab

Powder and solvent for solution for infusion

Intravenous use

Therapy began as soon as possible after the patient has been enrolled and preferably started on a Wednesday (w1d1) to allow timely initiation of RT on day 6 of treatment week 1 (w1d6). Patients received 240 mg nivolumab i.v. in 2-weekly intervals usually in an outpatient setting. The first infusion was administered over 60 minutes while consecutive infusions were administered over 30 minutes if no infusion related reaction was observed. Subjects were dosed no less than 12 days from the previous dose of drug and subsequent infusions should not have been delayed unnecessarily or without medical reasons. The patient should have been observed for 60 minutes following the first infusion of nivolumab. During this observation period, the i.v. line should have remained patent to allow administration of i.v. drugs if necessary. In case an infusion-related reaction have occured after reduction to 30 minutes infusion duration, the following nivolumab infusions had to be administered over 60 min.

Stage-2

Full Analysis Set (FAS)

The full analysis set (FAS) consists of all patients who qualify for enrollment into the trial and receive at least one dose of study drug.

Abscopal response analysis set (ARAS)

The ARAS consists of all FAS subjects who meet all evaluability criteria and none of the exclusion criteria stated below: Evaluability Criteria: Patient received one initial nivolumab dose before and at least 3 doses after the first fraction of RT, RT was timed and performed according to protocol. Exclusion Criteria: First Nivolumab dose more than 6 weeks after the scheduled treatment-interval of the last anti-PD1 infusion outside the trial, Less than 4 Nivolumab doses before week 12, RT start before the first nivolumab dose, RT start after the second nivolumab dose, >3 calendar days between any two consecutive RT treatment days, Less than 9 or more than 12 single RT doses, No Non-RTL outside the 10% isodose of RT, Start of non-study treatment before completion of RE-6 examinations. One patient withdrew informed consent and had no post-baseline assessment and was excluded from the ARAS.

Stage-2

Full Analysis Set (FAS)

The full analysis set (FAS) consists of all patients who qualify for enrollment into the trial and receive at least one dose of study drug.

Abscopal response analysis set (ARAS)

The ARAS consists of all FAS subjects who meet all evaluability criteria and none of the exclusion criteria stated below: Evaluability Criteria: Patient received one initial nivolumab dose before and at least 3 doses after the first fraction of RT, RT was timed and performed according to protocol. Exclusion Criteria: First Nivolumab dose more than 6 weeks after the scheduled treatment-interval of the last anti-PD1 infusion outside the trial, Less than 4 Nivolumab doses before week 12, RT start before the first nivolumab dose, RT start after the second nivolumab dose, >3 calendar days between any two consecutive RT treatment days, Less than 9 or more than 12 single RT doses, No Non-RTL outside the 10% isodose of RT, Start of non-study treatment before completion of RE-6 examinations. One patient withdrew informed consent and had no post-baseline assessment and was excluded from the ARAS.

The primary objective was to assess the ARR to localized RT combined with 4–6 doses of the study drug. An ARR ≤5% was considered insignificant, while an ARR of around 30% suggested a promising systemic effect in heavily pre-treated HL patients. Efficacy benchmarks were evaluated using Simon's optimal two-stage design. The null hypothesis (H0: ARR-6 < 5%) was tested against a one-sided alternative with a significance level of 5%. The probability of not rejecting H0 when the true ARR-6 was 30% was controlled at <5%. In stage 2, the UMVUE and two-sided 90% confidence limits for ARR-6 were calculated according to Koyama and Chen. The one-sided 95% confidence interval was obtained by setting the upper limit to 1. H0 was rejected if the lower limit exceeded 5%. Based on stage-1 results, the test had 100% power regardless of the final number of evaluable patients in stage 2.

Primary

Prerequisite of primary endpoint assessment is the first restaging which was performed and documented between weeks 12 – 14, after the last nivolumab dose administered before week 12 after start of treatment.

Abscopal response analysis set (ARAS) v Full Analysis Set (FAS)

49

Pre-specified

45.8

1-sided

The overall remission status (CR, PR, SD, PD) was listed for each subject and summarized per investigator.

Secondary

Consecutive restaging examination over the course of therapy with nivolumab doses (RE-6)

For subjects who survive without PD, the DOR was censored on the date of their last tumor assessment. Subjects who started subsequent therapy without a prior reported PD were censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy. This endpoint will only be evaluated in subjects with CR or PR.

Secondary

DOR was defined as the time from first response (CR or PR) to the date of first objectively documented disease progression (PD) or death due to any cause, whichever occurs first.

Failure-free survival (FFS) was calculated as time between the initiation of treatment with nivolumab within the trial and the date of first progression, relapse, death, or administration of any anti-cancer drug other than nivolumab or radiotherapy. If none of these events have occurred, FFS was censored on the date of the last documented staging or follow-up.

Secondary

One-year FFS (as reported) and 18-months FFS rates

Progression-free survival (PFS) was calculated for each as time between the initiation of treatment with nivolumab within the trial and the date of first progression, relapse or death. In cases of continuing response, PFS will be censored at the date of the last documented follow-up.

Secondary

One-year PFS rates (as reported) and 18-months PFS rates

Overall survival (OS) was calculated for each patient as time between the initiation of treatment with nivolumab within the trial and the date of death. In patients alive by the time of analysis, OS was censored at the date of the last documented information on survival status.

Secondary

One-year OS rates (as reported) and 18-months OS rates

All events from first dose up to 125 days after treatment end must be reported. Events beyond 125 days must be reported only if a causal relationship to study treatment is suspected.

During the period, every adverse event has to be documented, independent of the investigator’s opinion whether there is a causative relation with therapy or not.

10.1

Safety analysis set (SAS)