| 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 | 100000004864 |
|
| 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 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.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on specimens collected during this clinical trial (DNA, RNA, plasma from blood for plasma biomarker analyses, serum from blood for serum biomarker analyses, plasma from blood for ctDNA and main study tumor). Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal isto use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1. Must be between the ages of 3 and 25 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
Bulky disease is 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 a diagnostic CT, 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. A male participant must agree to use contraception during the treatment period and for at least 120 days (or longer, if required by the drug label of chemotherapy received by the participant on study) after the last dose of study treatment and refrain from donating sperm during this period
5. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP)
OR
b) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days (or longer, if required by the drug label of chemotherapy received by the participant on study) after the last dose of study treatment
6. The participant (or legally acceptable representative if applicable) provides written 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 and including 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 72 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. Has received any prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device before the first dose of study treatment, or has not recovered (≤Grade 1 or at baseline) from AEs due to previously administered agents
6. Is expected to receive a live vaccine within 30 days prior to the first dose of pembrolizumab. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
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. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy
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. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
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 known history of active tuberculosis (TB; Bacillus tuberculosis)
19. 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
20. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment |
|
| 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 | No |
| 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 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Colombia |
| Czechia |
| France |
| Germany |
| Greece |
| Guatemala |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| 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.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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