| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| cHL in children and young adults |
|
| E.1.1.1 | Medical condition in easily understood language |
| Classical Hodgkin lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10080208 |
| E.1.2 | Term | Classical Hodgkin lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
|
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate the rate of Positron Emission Tomography (PET) negativity, 2-year event-free survival (EFS) after study enrollment by IWG criteria as assessed by BICR, and overall survival (OS) of pembrolizumab in combination with chemotherapy in SERs by risk group
2.To evaluate the exposure to radiation therapy (RT) and its associated toxicity in SERs by risk group
3.To evaluate the rate of PET negativity per investigator assessment in Group 1 participants after completing 2 cycles of ABVD induction
4.To evaluate the 3-year EFS and OS in rapid early responders (RERs) by risk group
5.To evaluate serum TARC as a potential biomarker in SERs by risk group
6.To evaluate the safety of pembrolizumab in combination with chemotherapy in SERs by risk group
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be male or female between the ages of 3 and 25 years inclusive on the day of signing informed consent/assent
2. Group 1: Must have newly diagnosed, pathologically confirmed cHL at Stages IA, IB and IIA without bulky disease defined as the presence of any of the following:
- Nodal area >6cm OR
- Mass/thoracic diameter >one-third
Group 2: Must have newly diagnosed, pathologically confirmed cHL at Stages IIEB, IIIEA, IIIEB, IIIB, IVA and IVB
3. Must have measurable disease per investigator assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Measurable disease is defined as the existence of at least one measurable nodal lesion present, defined as a lymph node or nodal mass that is either >15 mm in longest diameter or >10 mm in short axis on anatomic imaging (ie, a diagnostic CT or MRI) and appropriate for reproducible measurements. A lesion that appears measurable, but is located in an area that was previously irradiated, can be considered measurable if it has shown growth since the completion of radiation
4.Male participants are eligible to participate if they agree to the following during the
interv period and for at least the time needed to eliminate each study interv after the last dose of study interv. The length of time required to continue contracep for each study intervention is:
- Pembrolizumab: no contraception requir
- Chemotherapy: refrain from donating sperm for 90 days after last dose of chemother
PLUS either:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent
OR
- Uses contraception unless confirmed to be azoospermic documented from the site personnel’s review of the participant’s medical records, medical examination,
or medical history interview as detailed below:
o uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
o Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
5. female participant is eligible to participate if she is not pregnant , not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and uses contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time
required to continue contraception for each study intervention is as follows:
o Vinblastine and Vincristine: 30 days
o Other Chemotherapies: 180 days
o Pembrolizumab: 120 days. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
Contraceptive use by women should be consistent with local
regulations regarding the methods of contraception for those participating in clinical
studies. If the contraception requirements in the local label for any of the study
interventions is more stringent than the requirements above, the local label
requirements are to be followed.
- has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study
intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Abstains from breastfeeding during the study at least 120 days after study intervention for
pembrolizumab and 180 days for chemotherapy, whichever is last.
Has had her medical history, menstrual history, and recent sexual activity reviewed
by the investigator to decrease the risk for inclusion of a woman with an early
undetected pregnancy
6. The participant (or legally acceptable representative if applicable) provides documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However the participant may participate in the main study without participating in FBR
7. Must have a performance status as defined below:
- Lansky Play-Performance Scale ≥50 for children up to 16 years of age
- Karnofsky score ≥50 for participants ≥16 years of age
8. Must have adequate organ function |
|
| E.4 | Principal exclusion criteria |
1. Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Participants who have had allogeneic hematopoietic stem cell transplant greater than 5 years ago are eligible as long as there are no symptoms of graft-versus-host disease (GVHD)
2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
3. Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, CD137) or has previously participated in a Merck pembrolizumab (MK-3475) clinical study
5. Received prior systemic anti-cancer therapy, including investigational agent
6.Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
7. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
8. Has a diagnosis of lymphocyte-predominant HL
9. Has a diagnosis of immunodeficiency or is expected to be receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be approved after consultation with the Sponsor
10. Has a known additional malignancy that is progressing or requires active treatment within the past 3 years
11. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator at the time of diagnosis
12. Has severe hypersensitivity (≥Grade 3) to any study therapies including any excipients
13. An active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid)
14. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
15. Has an active infection requiring systemic therapy
16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
18. 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
19. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
20. Participants who have not adequately recovered from major surgery or have ongoing
surgical complications. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Rate of Positron Emission Tomography (PET) Scan Negativity in SER Participants By Risk Group (Low, High) After AVD or COPDAC-28 Chemotherapy
2.Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR
3.Overall Survival (OS) in SER Participants By Risk Group (Low, High)
4.Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High)
5.Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy
6.EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator
7.OS in RER Participants By Risk Group (Low, High)
8.Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High)
9.Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High)
10.Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Up to 5 years
2.Up to 5 years
3.Up to 5 years
4.Up to 5 years
5.Up to 5 years
6.Up to 5 years
7.Up to 5 years
8.Up to 5 years
9.Up to 5 years
10.Up to 5 years
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Chile |
| Colombia |
| Guatemala |
| New Zealand |
| Peru |
| Ukraine |
| Hong Kong |
| Australia |
| Brazil |
| Canada |
| Israel |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| United Kingdom |
| United States |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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