Daratumumab + Radiation/Temozolomide for Glioblastoma

(PRIDE Trial)

Overseen By Sonikpreet Aulakh, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: West Virginia University

Must not be taking: BCG, Deferiprone, Dipyrone, others

Disqualifiers: Prior GBM treatment, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

16 Participants Needed

Trial Summary

What is the purpose of this trial?

TMZ is a standard therapy for GBM. The study will demonstrate that Daratumumab can collaborate with TMZ to enhance the cytotoxicity against GBM cells. Collectively, the preclinical data along with existing in vivo studies by others provides the rationale for therapeutic targeting of CD38 in GBM and its microenvironment. Daratumumab is commercially available, is safe and well tolerated when combined with alkylating chemotherapy, radiation therapy and has attained therapeutic CSF levels. Thus, the addition of Daratumumab to the frontline treatment regimen of GBM can potentially have a significant clinical benefit. Approximately 16 subjects will be enrolled in this trial. Up to 6 will be enrolled in the phase I part and 10 to 13 in the phase II part to come up with a total of 16 patients with 2 phases combined.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, certain drugs, especially those in risk categories X, D, and C, should be avoided or monitored when used with Daratumumab and TMZ. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Daratumumab when used with radiation and Temozolomide for treating glioblastoma?

Research shows that adding Temozolomide to radiation therapy improves survival in glioblastoma patients compared to radiation alone. This suggests that combining treatments can be more effective than using a single therapy. ^{1 2 3 4 5}

How does the drug Daratumumab combined with Radiation/Temozolomide differ from other treatments for glioblastoma?

Daratumumab combined with Radiation/Temozolomide for glioblastoma is unique because it incorporates an immunotherapy drug (Daratumumab) that targets specific proteins on cancer cells, potentially enhancing the immune system's ability to fight the tumor, alongside the standard chemotherapy (Temozolomide) and radiation. This combination aims to improve treatment efficacy by leveraging both direct tumor cell killing and immune system activation, which is different from traditional treatments that primarily focus on chemotherapy and radiation alone. ^{4 5 6 7 8}

Research Team

Sonikpreet Aulakh, MD

Principal Investigator

WVU Cancer Institute

Eligibility Criteria

This trial is for adults with glioblastoma (GBM) who haven't had prior treatment for it. They must be in good general health with proper organ and marrow function, not have severe illnesses or psychiatric conditions that could affect participation, and agree to use contraception. People with certain heart diseases, uncontrolled asthma, COPD, or a history of allergic reactions to similar drugs are excluded.

Inclusion Criteria

I agree to use birth control during the study.

My blood tests show normal organ function and I don't have severe kidney issues.

I have chronic hepatitis B but it's under control with treatment.

Exclusion Criteria

My lung function is less than half of what is expected for someone my age and size.

Patients receiving any other investigational agents

I have received treatment for brain cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery/Biopsy

Participants receive one dose of Daratumumab prior to surgery or biopsy

1 week

1 visit (in-person)

Treatment

Participants receive Daratumumab in combination with Temozolomide and radiation therapy

24 weeks

Weekly visits for 8 weeks, then bi-weekly visits until week 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 12 months

Treatment Details

Interventions

• Daratumumab

Trial Overview The study tests if adding Daratumumab to the standard GBM therapy of Temozolomide (TMZ) and radiation can better kill cancer cells. It's divided into two parts: an initial phase I with up to 6 participants followed by a phase II involving 10-13 more subjects.

Participant Groups

Group I: Daratumumab Experimental Treatment 1 Intervention

Daratumumab, IV, 16 mg/KG - 1 dose prior to surgery or biopsy; Weeks 1 - 8 = 1 dose weekly; Weeks 9 - 24 = 1 dose every other week; Weeks 25 onward (determined by disease progression) = 1 dose every 4 weeks

Who Is Running the Clinical Trial?

West Virginia University

Lead Sponsor

Trials

192

Recruited

64,700+

Findings from Research

Adding nitrosourea-based chemotherapy to radiotherapy has been shown to increase progression-free survival in patients with grade II and III gliomas, although it does not improve overall survival.

Upcoming phase III trials will investigate whether adding temozolomide to radiotherapy can enhance overall survival in grade II/III gliomas, while also assessing cognitive function and quality of life for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. Schiff, D.[2018]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

Depatuxizumab mafodotin (depatux-m) has an acceptable safety profile, with ocular toxicities being the most common side effects observed in 92% of patients, and a maximum tolerated dose of 1.5 mg/kg established for its combination with temozolomide.

In patients with recurrent glioblastoma, depatux-m showed promising preliminary efficacy, with a 6-month progression-free survival rate of 30.8% and a median overall survival of 10.7 months, indicating potential benefits for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Gan, HK., Reardon, DA., Lassman, AB., et al.[2023]

In a retrospective analysis of the AVAglio trial involving 921 glioblastoma patients, those with IDH1 wild-type proneural tumors showed a significant overall survival (OS) benefit from bevacizumab treatment compared to placebo, with an OS of 17.1 months versus 12.8 months.

While patients with mesenchymal and proneural tumors experienced progression-free survival (PFS) benefits from bevacizumab, only the proneural subtype demonstrated a corresponding OS advantage, highlighting the importance of molecular subtypes in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. Sandmann, T., Bourgon, R., Garcia, J., et al.[2022]

The combination of anti-GITR monoclonal antibody (mAb) and stereotactic radiosurgery (SRS) significantly improved survival rates in a mouse model of glioblastoma, with a cure rate of 24% compared to 0% for either treatment alone, indicating a strong immune-mediated effect.

The treatment with anti-GITR (1) and SRS led to increased infiltration of CD4+ effector T-cells and enhanced production of immune signaling molecules like IFNγ and IL-2, suggesting that this combination effectively shifts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. Patel, MA., Kim, JE., Theodros, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Temozolomide and radiation in low-grade and anaplastic gliomas: temoradiation. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Health-related quality of life in patients with glioblastoma: a randomised controlled trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Nimotuzumab in combination with radiotherapy in high grade glioma patients: a single institution experience. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Controversies in the adjuvant therapy of high-grade gliomas. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. [2022]