| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of advanced melanoma or advanced, relapsed or refractory PD-L1 positive malignant solid tumor or lymphoma in children from 6 months to less than 18 years old. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced childhood cancers including solid tumors, melanoma or 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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 |
For Advanced Melanoma, Advanced, Relapsed or Refractory Pd-L1 Positive Malignant Solid Tumor or Other Lymphoma, MSI-H Solid Tumor
Part I:
-To define the rate of dose-limiting toxicities (DLTs) at the maximum tolerated dose (MTD) or maximum administered dose (MAD) of pembrolizumab when administered as monotherapy to children from 6 months to < 18 years of age pooled across all indications
Part I and II:
-To determine the safety and tolerability of pembrolizumab based on AEs, and clinical and laboratory measures in children from 6 months to <18 years of age pooled across cohorts
For the Relapsed Refractory Classical Hodfkin Lymphoma Cohort
Part II:
-To determine the safety and tolerability of pembrolizumab based on AEs and clinical and laboratory measures in children with rrcHL.
-To evaluate anti-tumor activity of pembrolizumab in the rrcHL Cohort based on the ORR according to the IWG response criteria.
For a full list of objectives, please refer to the protocol. |
|
| E.2.2 | Secondary objectives of the trial |
For Advanced Melanoma, Advanced, Relapsed or Refractory Pd-L1 Positive Malignant Solid Tumor or Other Lymphoma, MSI-H Solid Tumor
Part I:
-To characterize the PK and pharmacodynamics of pembrolizumab administered as monotherapy to children from 6 mo to < 18 years of age pooled across cohorts/indications.
Part I and II:
-To evaluate clinical activity of pembrolizumab within each tumor type i in children form 6 mo of age
-To assess the change in vaccinated antibody concentrations, and memory B- and T-cell counts
-To evaluate the relationship between baseline tumor PD-L1 expression and clinical efficacy outcomes.
For Relapsed Refractory Classical Hodgkin Lymphoma
Part I and II:
-To evaluate anti-tumor activity of pembrolizumab in the rrcHL Cohort according to the IWG response criteria
-To assess the change in vaccinated antibody concentrations, and memory B- and T-cell counts
For a full list of objectives, please refer to the protocol |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. 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 is to 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. Be willing and able to provide (and/or their parents or legal guardians) written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be between 6 months and less than 18 years of age on the day the prescreen informed consent/assent is signed. Patients who do not require prescreening, must meet the age requirement on the day the main informed consent is signed.
3. Have histologically or cytologically-documented, locally-advanced, or metastatic solid malignancy that is incurable and has either (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient and treating physician. There is no limit to the number of prior treatment regimens.
4. Be able to provide tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated (tumors progressing in a prior site of radiation are allowed for characterization, other exceptions may be considered after Sponsor consultation). Samples that require decalcification are not allowed.
5. Have either advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma as determined by IHC in archival formal fixed paraffin embedded tumor (FFPET) or newly obtained biopsy. For this trial, tumor specimens with positive stroma or at least 1% of cells expressing PD-L1 by IHC will be defined as PD-L1 positive. (Subjects with PD-L1 negative tumors may be enolled in Part II of the trial in selet tumor types where preliminary response is observed)
6. Have measurable disease based on RECIST 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Subjects with neuroblastoma who do not have measurable disease per RECIST 1.1 but have MIBG-positive evaluable disease may be enrolled.
7. Have a performance status as defined below:
• Lansky Play Scale ≥50 for children up to and including 16 years of age;
• Karnofsky score ≥50 for children > 16 years of age
•Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
8. Demonstrate adequate organ function
9.Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
12. Six of the 12 subjects in a given dose finding/dose confirmation cohort (i.e. Part I) must weigh ≥16 kg (a minimum of 6 subjects at any given dose are needed for the IL--2 assay, and subjects must weigh ≥16 kg in order to provide a specimen for IL-2 analysis).
Subject Inclusion Criteria Relapsed or Refractory Classical Hodgkin Lymphoma Cohort
13. Be willing and able to provide (and/or their parents or legal guardians) written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research.
However, the subject may participate in the main trial without participating in Future Biomedical Research.
14. Be between 3 years and less than 18 years of age on the day the prescreen
informed consent is signed. Patients who do not require pre-screening, must meet
the age requirement on the day the main informed consent is signed.
15. Have relapsed* or refractory† cHL and are either:
- Refractory to front-line therapy;
- High-risk and relapsed from front-line therapy; or
- Relapsed or refractory to second-line therapy
*Relapsed: disease progression after most recent therapy
†Refractory: failure to achieve CR or PR
16. Be able to provide lymph node biopsy tissue from an archival sample or newly obtained biopsy of a tumor lesion not previously irradiated
17. Have a performance status as defined in the protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy in, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of allocation/randomization.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the date of allocation/randomization. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent)
may be approved after consultation with the Sponsor.
3. Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at baseline) from adverse events due to
a previously administered agent.
4. Has received prior radiotherapy within 2 weeks of start of trial treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (≤2
weeks of radiotherapy) to non-CNS disease.
5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially
curative therapy are not excluded.
6. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (Of note, subjects with tumors involving the brain stem are excluded from the study.
7. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
8. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
9. Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality, that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion
of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 120 days after the last dose of trial treatment.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)."Subjects with
melanoma who previously received treatment with ipilimumab are not
excluded.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV
1/2 antibodies). No HIV testing is required unless mandated by local health authority.
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). No testing for Hepatitis B and Hepatitis C is requiredunless mandated by local health authority.
17. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
18. Has received a live vaccine within 30 days of planned start of trial drug. 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 (BCG), and typhoid
vaccine. Seasonal influenza vaccines for injection are generally killedvirus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
19. Has undergone solid organ transplant at any time, or prior allogeneic
hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a nallogeneic hematopoietic transplant greater than 5 years ago are eligible as long as there are no symptoms of GVHD.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is objective response rate, defined as the proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) using RECIST 1.1 at any time during the study using RECIST 1.1 for solid tumors and other lymphoma. Response for the primary analysis will be determined by the investigator assessment, and a confirmation assessment is required per RECIST 1.1.
For the RRCHL Cohort, the primary efficacy endpoint is ORR, defined as the proportion of subjects in the analysis population who have a CR or PR at any time during the study using IWG. Response for the primary analysis for the rrcHL Cohort will be determined by the blinded independent central radiology assessment.
The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab, including serious adverse events (SAEs). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety Endpoints: Dose limiting toxicities will be evaluated in the first cycle of treatment (Q3W dosing) or the first two cycles of treatment (Q2W dosing). Safety endpoints will be evaluated for all treated subjects from initiation of treatment through the protocol defined safety follow-up period of 90 days for SAEs (unless a given subject initiates new anti-cancer therapy, in which case the follow-up period for that subject is 30 days)
Efficacy Endpoints: Efficacy will be evaluated every 8 weeks after initiation of trial treatment until disease progression.
|
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include: (1) duration of response, defined as time from first RECIST 1.1 response to documented PD, death due to any cause, or start of new anti-cancer therapy, whichever occurs first, in subjects who achieve a PR or better; (2) progression-free survival (PFS), defined as the time from the first dosing date to the first documented disease progression according to RECIST 1.1 or death due to any cause, or start of new anti-cancer therapy, whichever occurs first; (3) disease control rate, defined as the proportion of subjects with best overall response of complete responses (CR), partial responses (PR), or stable disease (SD), and (4) overall survival (OS).
Additional supportive analyses of objective overall response rate, duration of response, and PFS will be conducted using a modified RECIST 1.1 criteria (irRECIST), in which a confirmation assessment of disease progression must be obtained at least 4 weeks after the initial disease assessment indicating progressive disease. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy will be evaluated every 8 weeks after initiation of trial treatment until disease progression. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose Finding with Confirmation in Phase I |
|
| 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.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Chile |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Sweden |
| 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
|
| The end of study may be designated as the time point when all subjects have discontinued the study or are a minimum of 6 months post initial study medication administration. If there remains at least 1 subject still on treatment for at least 6 months, the subject may enter additional treatment cycles. At this point a database lock of the trial may occur to allow the analysis. Any remaining subjects may continue to receive medication and be seen by the investigator per usual standard of care. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 0 |
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