Phase 1/2 Evaluation of Cobolimab and Dostarlimab in Pediatric and Young Adult Patients with Newly Diagnosed and Relapsed/Refractory Solid Tumors

Trial ID: 2024-511350-41-00
Protocol: 219451
Sponsor: Glaxosmithkline Research & Development Limited

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Diseases & Conditions

Hodgkin's disease Hepatic cancer Rhabdomyosarcoma Malignant melanoma

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of cobolimab in combination with dostarlimab in pediatric and young adult participants with advanced solid tumors. Additionally, the study aims to determine the recommended Phase 2 dose (RP2D) of this combination therapy. These objectives are clinically relevant as they provide critical information on the potential risks and appropriate dosing of the investigational drugs, which is essential for ensuring patient safety and optimizing therapeutic efficacy in subsequent phases of clinical development.

Secondary objectives include:

Part 1: To evaluate target engagement (pharmacodynamics) of cobolimab in combination with dostarlimab.
Part 1: To evaluate the measures of clinical benefit of cobolimab in combination with dostarlimab.
Part 1: To evaluate immunogenicity (ADA) of cobolimab and dostarlimab in pediatric and young adult participants with advanced solid tumors.
Part 2: To evaluate additional measures of clinical benefit for cobolimab in combination with dostarlimab in pediatric and young adult participants with melanoma, Hodgkin lymphoma, and other selected pathologies.
Part 2: To evaluate the pharmacokinetic (PK) profile of cobolimab in combination with dostarlimab.
Part 2: To evaluate pharmacodynamics of cobolimab in combination with dostarlimab.
Part 2: To evaluate immunogenicity (ADA) of cobolimab and dostarlimab.

These secondary objectives are important for understanding the biological activity, potential clinical benefits, and immune response associated with the treatment, which can inform future therapeutic strategies and patient management.

Participants

The clinical trial involves a total of **109 participants** who are pediatric and young adult individuals diagnosed with **relapsed/refractory tumors**. The study population includes both male and female subjects, with age ranges specified for different cohorts: Part 1 includes participants from 0 to less than 18 years, while Part 2 includes those from 6 to less than 21 years. Participants were selected based on their advanced or metastatic solid tumor status, having experienced disease progression after available therapies, and possessing limited treatment options. The trial includes individuals with conditions such as melanoma, Hodgkin lymphoma, gliomas, osteosarcoma, hepatic tumors, and rhabdomyosarcoma. Participants are required to have a performance status of at least 60% on the Karnofsky or Lansky scale, depending on age, and must demonstrate adequate organ function. Lifestyle considerations such as contraceptive use are mandated for adolescent participants who have entered puberty. The trial population is considered vulnerable, and informed consent is obtained from participants or their legal representatives. The study does not specify any particular dietary or physical activity requirements for participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the safety, tolerability, and efficacy of **cobolimab** in combination with **dostarlimab** in pediatric and young adult participants with newly diagnosed and relapsed/refractory tumors. The trial is divided into two parts: Part 1 focuses on dose determination and safety evaluation, while Part 2 assesses the anti-tumor activity in specific cohorts, including melanoma, Hodgkin lymphoma, and other selected pathologies. The trial is expected to commence recruitment in November 2024 and conclude by November 2030, with the overall duration spanning approximately six years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease characteristics, and organ function. Following successful screening, participants will be enrolled and randomized into treatment groups. Regular follow-up visits will be scheduled to monitor safety, collect pharmacokinetic data, and evaluate treatment efficacy. These visits will include assessments of adverse events, laboratory parameters, and imaging studies to measure tumor response. The end-of-study visit will occur after the final treatment cycle or upon early termination, where comprehensive evaluations will be conducted to gather final safety and efficacy data.

The expected length of participant involvement varies depending on individual response and tolerance to the treatment, with early termination possible in cases of unacceptable toxicity, disease progression, or withdrawal of consent. Participants will be closely monitored for dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs), with specific criteria in place to ensure participant safety. The study aims to determine the recommended Phase 2 dose (RP2D) and to evaluate the overall response rate (ORR) and progression-free survival (PFS) among other endpoints. The trial will adhere to rigorous ethical standards, with informed consent obtained from all participants or their legal representatives prior to any study-related procedures.

Treatment

The clinical trial involves the administration of two experimental medications: **dostarlimab** and **cobolimab**. **Dostarlimab** is provided as a 500 mg concentrate for solution for infusion, marketed under the name JEMPERLI. It is manufactured by GlaxoSmithKline (Ireland) Limited. The pharmaceutical form is a concentrate for solution for infusion, and it is administered via **intravenous infusion**. The dosing schedule and frequency of administration are determined based on the study protocol, with the use of a closed system transfer device permitted for the transfer of the 50 mg/mL solution in a clinical setting. Compatibility details are provided within the study's supplementary documentation.

**Cobolimab** is also administered as a solution for infusion, with GlaxoSmithKline as the manufacturer. The active substance is classified as a protein of other origin, similar to dostarlimab. The administration route is **intravenous infusion**, and the dosing schedule is aligned with the study's objectives to evaluate safety, tolerability, and pharmacokinetic profile in combination with dostarlimab. Both medications are not formulated for pediatric use, and their role in the trial is to assess their combined effect on pediatric and young adult participants with advanced solid tumors.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. Participant compliance with the dosing regimen is monitored according to the study protocol, ensuring adherence to the administration guidelines. The trial aims to determine the recommended phase 2 dose (RP2D) of the combination therapy, with a focus on evaluating anti-tumor activity in specific cohorts, including melanoma and Hodgkin lymphoma.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part 1 include the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), immune-mediated adverse events (imAEs), and adverse events (AEs) leading to discontinuation. Additionally, the serum concentrations of the investigational medicinal product (IMP) will be measured up to Cycle 6, and the recommended Phase 2 dose (RP2D) will be determined. For Part 2, the primary endpoints include the confirmed objective response rate (ORR), the incidence of TEAEs, SAEs, imAEs, TEAEs leading to death, and AEs leading to discontinuation, as well as changes in safety assessments such as laboratory parameters, vital signs, and cardiac parameters.

Secondary endpoints for Part 1 include receptor occupancy measured in whole blood as a normalized free-to-total TIM-3 receptor ratio, confirmed ORR, progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence and titers of anti-drug antibodies (ADAs) against **cobolimab** and **dostarlimab**. For Part 2, secondary endpoints include PFS, DOR, OS, serum concentrations of **cobolimab** and **dostarlimab**, receptor occupancy, and the incidence and titers of ADAs against the investigational drugs.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants must meet the following age criteria at the time of signing the ICF: • Part 1: Cohort 1a: 12 years to <18 years; Cohort 1b: 6 years to <12 years; Cohort 1c: 2 to <6 years; Cohort 1d: 0 to <2 years. • Part 2: Cohort A: 6 to <21 years; Cohort B: 6 to <21 years; Cohort C: Age to be decided.
Type of participants and disease characteristics: • Part 1: Participants with advanced or metastatic solid tumors who have had disease progression after treatment with available therapies that are known to confer clinical benefit and who have limited available treatment options as determined by the investigator. Additionally, exposure to prior immunotherapy or experimental therapies is acceptable: Melanoma; Hodgkin Lymphoma; High and Low Grade Glioma: including GBM, DIPG, and ependymoma; Osteosarcoma; Hepatic tumors (including Hepatoblastoma, HCC, and Fibrolamellar carcinoma); Rhabdomyosarcoma. • Part 2: Cohort A: Melanoma patients who have not received prior systemic therapy: − Participants with BRAF mutations who are eligible for a BRAF-targeted therapy are eligible if they qualify for immunotherapy. − Participants with locally treated and controlled metastatic CNS lesions without leptomeningeal spread are eligible. Cohort B: Hodgkin lymphoma - Relapsed/refractory Hodgkin lymphoma that has failed at least 2 prior lines of systemic therapy). Cohort C: Indication/s to be decided based on Part 1 results.
Participant has measurable disease, that is, presenting with at least 1 measurable lesion as determined by the local site Investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if disease progression has been demonstrated in such lesions and if there are other target lesions. If there is only 1 target lesion that was previously irradiated, the participant is not eligible. Eligible HL participants must have at least one FDG-avid lesion, preferably with higher intensity than normal liver.
Participants must have performance status ≥60% on the Karnofsky scale for participants >16 years of age and ≥60% on the Lansky scale for participants ≤16 years of age.
Adequate organ function as demonstrated by a complete blood count at screening obtained without transfusion (platelets or RBC) or receipt of CSF, G-CSF, GMCSF or rEPO within 2 weeks prior to screening labs, with the following results: • ANC ≥1,000/μL; • platelets ≥75,000/μL; • hemoglobin ≥9 g/dL or ≥5.6 mmol/L; • glomerular filtration rate ≥50 mL/min; • AST <2.5 × ULN; • ALT <2.5 × ULN; • bilirubin ≤1.5 × ULN; • international normalized ratio or PT ≤1.5×ULN unless the participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; • activated PTT ≤1.5×ULN unless the participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
Adolescent participants who have entered puberty must consent (be willing) to use of contraceptive measures, or refrain from sexual intercourse, if in line with their usual practice, as well as sperm/egg donation for the duration of treatment as described below: Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of non-childbearing potential (WONCBP) OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), during the study intervention period and for at least 150 days after the last dose of study intervention. A WOCBP must 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 (e.g., an ambiguous result), a serum pregnancy test is required.
The Investigator, or a person designated by the Investigator, will obtain written informed consent/assent from each study participant or the participant’s legally acceptable representative, parent(s), or legal guardian and the participant’s assent, when applicable, before any study specific activity is performed.

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Exclusion Criteria

Participant has uncontrolled CNS involvement by any tumor pathology (this would include leptomeningeal disease, and/or any new or progressive symptoms).
Participant has a heart rate-corrected QT interval according to QTcF prolongation at screening >470 msec or >480 msec for participants with bundle branch block.
Participant has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, cardiac arrhythmia, Grade 2 or greater congestive heart failure according to New York Heart Association if a young adult or adolescent or the modified Ross Heart Failure Classification in infants and children, serious cardiac arrhythmia requiring medication, and history of cerebrovascular accident) within 6 months of enrolment.
Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
Participant has a history of other malignancies prior to study entry, except for: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and with no evidence of disease recurrence for 2 years since the initiation of that therapy.
Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
Participant who have a history of immunodeficiency disease, including other acquired or congenital immunodeficiency diseases, or organ transplantation.
Participants who have received plasma exchange within 7 days before the first dose of study intervention.
Has current active pneumonitis or any history of pneumonitis requiring steroids or immunomodulatory treatment within 90 days of planned enrollment or any history of drug-induced pneumonitis.
Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening. Participants with prior history of autoimmune disease must be discussed with the medical monitor. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary).
Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, excluding [e.g., alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy], or that the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition ( that could affect the participant’s safety).
Has any serious and/or unstable medical or psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant’s safety, obtainment of informed consent, or compliance to the study procedures.
Participant has received treatment with an investigational agent or any other anti-cancer therapy within 30 days, or <5 times the half-life of the most recent therapy prior to signing ICF, whichever is shorter
Participant has received systemic steroid therapy within 3 days prior to the first dose of the study treatment or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed. Note: Low dose prednisone (up to 5 mg daily) or dexamethasone (up to 0.8 mg daily), or equivalent, as needed to manage certain chronic medical conditions, is allowed.
Participant has received any live attenuated vaccine within 30 days of enrollment.
Vaccination against COVID-19 using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live.
Participant has not met the following waiting/washout periods for external beam radiation therapy (XRT)/external beam irradiation including protons: Fourteen days after local palliative radiation therapy; ≥150 days after total body irradiation, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation.
Participant has had major surgery within 28 days prior to the first dose of study treatment or has not adequately recovered from any AEs (Grade ≤1) and/or complications from any major surgery. Surgical implantation of a port catheter is not exclusionary.
Prior Bone Marrow Transplant <60 days of screening.
Participant has experienced Grade 3 or higher hypersensitivity to prior monoclonal antibody therapy.
Participant is currently enrolled or has participated in any other clinical study involving an investigational study or interventional medical research within 21 days or 5 half-lives, whichever is shorter, of an investigational medicinal product before signing ICF.
Ongoing drug or alcohol abuse.
Participant has a documented presence of Hepatitis B surface antigen (HbsAg) at Screening or within 3 months prior to first dose of study intervention. Participants with a negative HbsAg and positive hepatitis B core antibody (HbcAb) result are eligible only if HBV DNA is negative.
Participant has a positive HCV antibody test result at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled, only if a confirmatory HCV RNA test is negative
Participant has a positive HCV RNA test result at Screening or within 3 months prior to first dose of study intervention. NOTE: The HCV RNA test is optional and participants with negative HCV antibody test are not required to undergo HCV RNA testing as well.
Participant has a known history of HIV or has a HIV-positive test result at Screening.
Participant is pregnant or breastfeeding.
Participant is unable to adhere to the protocol-defined Schedule of Activities, including requirements for the Follow-up Period of the study.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	01 Nov 2024	4
Denmark	Not Recruiting	01 Nov 2024	3
France	Not Recruiting	01 Nov 2024	12
Germany	Not Recruiting	01 Nov 2024	9
Italy	Not Recruiting	01 Nov 2024	9
Spain	Not Recruiting	01 Nov 2024	9