This study has been transitioned to CTIS with ID 2023-504821-38-00 check the CTIS register for the current data. Goal of this study is to determine the optimal balance between maintaining high rates of OS in this group and avoiding the long-term…
ID
Source
Brief title
Condition
- Lymphomas Hodgkin's disease
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objective: To evaluate the objective response rate (ORR) by International
Working Group (IWG) criteria as assessed by blinded independent central review
(BICR) [Cheson, B. D., et al 2007] of pembrolizumab in combination with
chemotherapy in slow early responders (SERs) by risk group (low, high)
Objective response: Complete response (CR) or partial response (PR)
Secondary outcome
(1)
Objective: To evaluate the rate of PET-negativity, 2-year event-free survival
(EFS) from study enrollment, and overall survival (OS) of pembrolizumab in
combination with chemotherapy in SERs by risk group.
Objective reponse:
- PET negativity: Deauville score (1, 2 or 3) after 2 cycles of AVD or 4 cycles
of COPDAC-28, in combination with pembrolizumab.
- EFS: Time from study enrollment to the first documented disease progression
or recurrence, or death due to any cause, whichever occurs first.
- OS: Time from study enrollment to death due to any cause
(2)
Objective: To evaluate the exposure to radiation therapy (RT) and its
associated toxicity in SERs by risk group
Objective response:
- Exposure to RT: Frequency and details of RT
(3)
Objective: To evaluate of the 3-year EFS per investigator assessment and OS in
rapid early responders (RERs) by risk group.
Objective response:
- EFS: Time from study enrollment to the first documented disease progression
or recurrence, or death due to any cause, whichever occurs first.
- OS: Time from study enrolment to death due to any cause
(4)
Objective: To evaluate serum thymus and activation-regulated chemokine (TARC)
as a potential biomarker in SERs by risk group.
Objective reponse:
- Serum TARC levels at screening, early and late response assessments.
(5)
Objective: To evaluate the safety of pembrolizumab in combination with
chemotherapy in SERs by risk group.
Objective reponse:
- Participants experiencing adverse events (AEs)
- Participants discontinuing study treatment due to AEs
Background summary
Although current treatment for Hodgkin Lymphoma patients results in high 5
years survival rates, a subgroup of cHL patients remains from which initial
cure rates are suboptimal. For both adults and children, this group is
identified as slow early responders to chemotherapy. As a result, many
cooperative groups have used the strategy of dose intensification with
chemotherapy and/or radiation to achieve comparable survival rates, however an
increase of (longterm) toxicity occured in these patients.
In the Pediatric Oncology Group (POG) 9425 and 9426 trials, a more intense
chemotherapy was used for those who sustained an inadequate response to
frontline chemotherapy. The French Society of Pediatric Oncology added an extra
dose of of radiotherapy (RT) and/or chemotherapy based on early response to
their chemotherapy backbone. In POG 9425, comparable results were found upon
tailoring therapy to the response, with no statistical difference in 3-year
event-free survival (EFS) for 3 versus 5 cycles of chemotherapy.
In AHOD0831, additional chemotherapy, 2 cycles of ifosfamide plus vinorelbine,
were associated with increased exposure to alkylating agents and associated
toxicity.
It was increasingly apparent that the comparable cure rates were bought at a
high price and that this dose intensification was associated with significant
risk of premature second malignancies, cardiovascular disease, pulmonary
toxicity, gonadal and nongonadal toxicity and early mortality [Castellino, S.
M., et al 2011].
Study objective
This study has been transitioned to CTIS with ID 2023-504821-38-00 check the CTIS register for the current data.
Goal of this study is to determine the optimal balance between maintaining high
rates of OS in this group and avoiding the long-term toxicity associated with
therapy intensificiation. The addition of pembrolizumab to standard care is
expected to overcome resistance to the initial agens and to prevent long term
complications associated with the initial agents.
Study design
This is a nonrandomized, open-label study with two groups of patients at a
single center to evaluate the effect and longterm toxicity after therapy with
pembrolizumab combined with 4 cycles of COPDAC-28 chemotherapy, followed by RT,
with or without pembrolizumab, in cHL patients with a slow, early response to
first-line chemotherapy.
Intervention
Patients complete 2 cycles of OEPA induction chemotherapy to determine the
Deauville score, as asessed by PET. Patients with score 4 or 5 (ie, SERs) will
receive pembrolizumab in combination with 4 cycles of COPDAC-28. The patients
will have a their PET scores assessed again after completing COPDAC-28
chemotherapy; patients with a positive PET-score will then receive RT while
continuing their pembro treatment, while patients with a negative PET response
will continue their pembro treatment without receiving RT.
Study burden and risks
Participants in this clinical study are not garantueed to directly benefit from
treatment during participation. However, the investigational agent
pembrolizumab, inhibitor of PD-1 signaling, has been registered for adult
patients with relapse/refractory cHL. Based on current evidence, no difference
in mechanism of action and activity are expected in cHL between children and
adults. In addition, the safety profile of pembrolizumab in pediatric patients
was similar to that seen in adults. Therefore, pembrolizumab has the potential
to offer children with newly diagnosed cHL a therapy that is expected to be
well tolerated and in addition may improve the response to early chemotherapy
and reduce cumulative drug toxicity.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
Type of participants and disease characteristics
- Must be a male or female between the age 3-25 years inclusive on the day of
signing informed consent/assent
- Newly diagnosed, pathologically confirmed classical Hodgkin Lymphoma: stage
IIEB, IIIEA, IIIEB, IIIB, IVA, IVB
- Measurable disease per investigator assessment
Contraception
- Male participants are eligible to participate if they agree to follow the
contracaption guidance clarified in the protocol. The lenght of time required
to continue contraception after the last dose for each study intervantion is
clarified in the protocol.
- A female participant is eligible if she is not pregnant, not breastfeeding
and not a woman of chilbearing potential OR agreeing to follow contraceptive
guidance according to protocol.
Informed consent
- The participant (or legally acceptable representative if applicable) provides
written informed consent/assent for the study
Additional Criteria
- Performance status:
- Lansky Play-Performance Scale >=50 for children up to 16 years of age
-Karnofsky score >=50 for participants >=16 years of age
- Adequate organ function
Exclusion criteria
Medical Conditions
- Has undergone solid organ transplant at any time, or prior allogeneic
hematopoietic stem cell transplantation within the last 5 years.
- A WOCBP who has a positive urine pregnancy test within 24 hours before the
first dose of study treatment.
- Baseline left ventricular ejection fraction value <50% or shortening fraction
of <27%
Prior/Concomitant Therapy
- Has received prior therapy with anti-PD1/PD-L1/PD-L2 or with an agent
directed to another co-inhibitory T cell receptor or has previously
participated in a Merck pembro clinical study
- Received prior systemic anti-cancer therapy, including investigational agent
- Received a live or live-attenuated vaccine within 30 days before the first
dose of study intervention.
Prior/Concurrent Clinical Study Experience
- Has received an investigational agent or has used an investigational device
within 4 weeks prior to study intervention administration
Diagnostic assessments
- Has a diagnosis of lymphocyte-predominant HL
- Has a diagnosis of immunodeficiency or is expected to be receiving chronic
systemic steroid therapy or any other immunosuppressive therapy within 7 days
prior to the first dose of pembro.
- Has a known additional malignancy that is progressing or requires active
treatment within the past 3 years
- Has radiographically detectable central nervous system metastases and/or
carcinomatous meninginitis as assessed by local site investigator at the time
of diagnosis.
- Has severe hypersensitivity to any study therapies including any excipients.
- Has an active autoimmune disease that has required systemic treatment in past
2 years except replacement therapy.
- Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has a known history of Hepatitis B or known active Hepatitis C virus
infection.
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in
the best interest of the participant to participate, in the opinion of the
treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
- Participants who have not adequately recovered from major surgery or have
ongoing
surgical complications.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-504821-38-00 |
| EudraCT | EUCTR2017-001123-53-NL |
| ClinicalTrials.gov | NCT03407144 |
| CCMO | NL72212.041.20 |