Study Overview

This is a Phase II Interventional Unblinded Open Blinded study. Treatment of cHL in children and young adults – evaluation of pembrolizumab in a subgroup with inadequate early response to frontline chemotherapy. Children 3 to 17 years of age and young adults 18 to 25 years of age with newly diagnosed cHL The Sponsor estimates that the study will require approximately 6 years from the time the first participant signs the informed consent/assent until the last participant’s last studyrelated contact or visit. Arkansas Children’s Research Institute Protocol Advertisement Form Updated 12/13/2019 Arkansas Children’s Hospital will only be participating in Group 1 (low risk) defined as participants with cHL stages IA, IB and IIA without bulky disease. After completing 2 cycles of ABVD induction chemotherapy, those with a Deauville score of 4 or 5 (ie, SERs), as assessed by PET, will receive pembrolizumab 2 mg/kg up to a max of 200 mg (3 to 17 years of age) or 200 mg (18 to 25 years of age) Q3W, in combination with 2 cycles of AVD (doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2 on days 1 and 15; cycle frequency: Q4W). Slow early responders will have their PET response assessed again after completing AVD chemotherapy. All SERs will then receive RT while continuing their pembrolizumab treatment.

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

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.

Contraception

4. A male participant must agree to use contraception as detailed in Appendix 7 of this protocol 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 (see Appendix 7), not breastfeeding, and at least one of the following conditions applies:

a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 7 OR Updated 12/13/2019

b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 7 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. 

Additional Criteria

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

Note: Participants 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. Must have adequate organ function as defined in Table 1. Specimens must be collected within 7 days prior to the start of trial treatment.

9. Table 1 Adequate Organ Function Laboratory Values

Pembrolizumab Clinical Trial Chart

Medical Conditions

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 (see Appendix 7). 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.

Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for the participant to start receiving study medication.

3. Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%.

Prior/Concomitant Therapy

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.
 
Note: Participants with ≤Grade 2 neuropathy are an exception and may qualify for the study.
Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

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.

Prior/Concurrent Clinical Study Experience

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.

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Diagnostic assessments

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.

Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

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.

Other Exclusions

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.

Note: The 120-day requirement may be extended to conform to the drug label of chemotherapy received by participants on study.

 

Contact

For more information about this study, contact Catherine Redinger at 501-364-4290 RedingerCatherineL@uams.edu or Suzy Hall at 501-364-4181 or Hallsf@archildrens.org.