What is the mechanism of action of this treatment?

Pembrolizumab, a PD-1 inhibitor, enhances the immune system's ability to attack tumor cells by blocking the PD-1 pathway, which cancer cells use to evade immune detection. Olaparib, a PARP inhibitor, prevents cancer cells from repairing their DNA, leading to cell death, especially in cells with existing DNA repair deficiencies. Temozolomide, an alkylating agent, damages the DNA of cancer cells, preventing their replication and leading to cell death. These treatments are significant for Glioblastoma patients as they target the cancer cells' growth and survival mechanisms, potentially improving outcomes in this aggressive and challenging disease.

What side effects are associated with this type of intervention?

The most common treatments for Glioblastoma, such as Pembrolizumab (a PD-1 inhibitor), Olaparib (a PARP inhibitor), and Temozolomide (an alkylating agent), have distinct side effect profiles. Pembrolizumab can cause immune-related adverse effects including pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions. Olaparib is associated with nausea, fatigue, anemia, and other hematologic toxicities. Temozolomide commonly causes nausea, vomiting, fatigue, and myelosuppression, which can lead to increased risk of infection. Patients should discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

Temozolomide, an alkylating agent, has been FDA-approved for the treatment of newly diagnosed Glioblastoma in combination with radiotherapy and as maintenance therapy. Pembrolizumab, a PD-1 inhibitor, has shown promise in various cancers but is not specifically FDA-approved for Glioblastoma. Olaparib, a PARP inhibitor, is approved for certain types of ovarian and breast cancers but not specifically for Glioblastoma. The combination of these drugs is currently being studied in clinical trials for their potential efficacy in treating recurrent Glioblastoma.

What other types of research exist?

Promising novel alternatives for Glioblastoma treatment in 2024 include: 1) Nivolumab (another PD-1 inhibitor) which has shown activity in recurrent meningioma and could be explored for Glioblastoma. 2) Atezolizumab (PD-L1 inhibitor) which has shown efficacy in NSCLC with brain metastases and could be considered for Glioblastoma. 3) Bevacizumab (angiogenesis inhibitor) which has been evaluated in various brain tumors and could offer benefits in Glioblastoma. 4) Everolimus (mTOR inhibitor) which has shown promise in meningioma and could be explored for Glioblastoma. These alternatives are based on their mechanisms and recent clinical trial data.

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PARP Inhibitor

Pembro + Olaparib with TMZ for Recurrent Glioblastoma

Phase 2

Recruiting

Led By Luis N Gonzalez Castro, MD

Research Sponsored by Patrick Wen, MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants must be able to swallow oral medications.

Participants must have histologically World Health Organization Grade IV IDH wildtype glioblastoma by IDHR132H immunohistochemistry or variants including gliosarcoma or IDH wildtype diffuse glioma with molecularly features of glioblastoma (EGFR amplification, TERT promoter mutation, or concurrent gain of Chromosome 7 and loss of Chromosome 10) (Brat et al., 2018). IDH mutational status can be established via immunohistochemistry and/or next-generation sequencing.

Must not have

Participant received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF0], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention.

Participants who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 24 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of three drugs to treat brain tumors that have come back after previous treatments. The drugs help the immune system attack the tumor, stop the tumor cells from repairing themselves, and prevent them from growing. About 66-78 people will participate in this study.

Who is the study for?

This trial is for adults with recurrent glioblastoma, a type of brain tumor. They must be in good physical condition (KPS ≥ 70), not pregnant or breastfeeding, able to swallow pills, and have adequate organ function. Patients should be at their first or second relapse and haven't had certain prior treatments like anti-PD-1 or PARP inhibitors.

What is being tested?

The study tests a combination therapy using Pembrolizumab, Olaparib, and Temozolomide as potential treatments for recurrent glioblastoma. It aims to see if this mix can stop the tumor from growing after previous treatment has failed.

What are the potential side effects?

Possible side effects include immune system reactions that might affect organs, fatigue, nausea, blood-related issues such as anemia or clotting problems. Each patient may experience these differently.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can swallow pills.

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My brain tumor is a Grade IV glioblastoma without IDH mutation.

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I am at least 18 years old.

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I am not pregnant or breastfeeding.

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I am mostly independent and can carry out daily activities.

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I am mostly independent and can carry out daily activities.

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My brain tumor is a Grade IV glioblastoma without IDH mutation.

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My brain cancer has returned for the first or second time.

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My latest MRI shows my tumor has grown.

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I do not have another cancer that is getting worse or needs treatment.

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I can swallow pills.

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My MRI shows my tumor has grown according to specific criteria.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have not received any colony-stimulating factors in the last 28 days.

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I have previously received immunotherapy targeting specific immune checkpoints.

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I am not taking medication that strongly affects enzyme CYP3A.

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My cancer has spread to the lining of my brain or other parts of my body.

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I have been diagnosed with an immunodeficiency or HIV.

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I am currently taking blood thinners like warfarin.

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I am allergic to medications similar to olaparib, temozolomide, or pembrolizumab.

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I haven't taken high doses of steroids like dexamethasone (>2 mg/day) for 3 days in a row within the last 2 weeks.

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I have a history of lung inflammation not caused by an infection.

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I have a heart condition that is currently causing symptoms.

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I have had viral therapy or vaccines for my brain tumor.

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I do not have any ongoing serious illnesses that could interfere with the study.

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My tumor is mainly in my brainstem or spinal cord.

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I have an active infection needing treatment or a known viral infection like HIV or hepatitis.

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My tumor has a 1p/19q co-deletion.

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I have an autoimmune disease treated with medication in the last 2 years.

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I have or might have a blood disorder related to MDS or AML.

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I have an active tuberculosis infection.

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I have been treated with drugs targeting blood vessel growth in cancer.

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I have previously been treated with a PARP inhibitor.

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I am currently taking medication for epilepsy.

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My cancer has an IDH mutation.

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I haven't taken immune-weakening drugs (except steroids) in the last 6 months.

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I have moderate to severe diarrhea.

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I have a history of heart problems.

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I haven't had serious bleeding or blood clotting issues in the past year.

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I am currently using herbal medications.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 24 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~24 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 24 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

6-month Progression-Free Survival (PFS6)

Tumor infiltrating lymphocytes (TIL) Density

Secondary study objectives

Gene expression profiling (GEP) score

Grade 3 or Higher Treatment-Related Toxicity Rate

Median Overall Survival (OS)

+1 more

Side effects data

From 2024 Phase 3 trial • 804 Patients • NCT03040999

64%

Radiation skin injury

63%

Stomatitis

58%

Anaemia

56%

Nausea

48%

Dry mouth

45%

Constipation

45%

Weight decreased

44%

Dysphagia

42%

Neutrophil count decreased

33%

Dysgeusia

33%

Vomiting

32%

Fatigue

31%

White blood cell count decreased

28%

Hypomagnesaemia

26%

Decreased appetite

25%

Hypothyroidism

25%

Hypokalaemia

24%

Lymphocyte count decreased

24%

Platelet count decreased

23%

Oropharyngeal pain

23%

Blood creatinine increased

22%

Diarrhoea

22%

Odynophagia

20%

Hypoacusis

20%

Alanine aminotransferase increased

20%

Hyponatraemia

19%

Tinnitus

19%

Oral candidiasis

19%

Asthenia

16%

Pyrexia

16%

Cough

15%

Aspartate aminotransferase increased

15%

Rash

14%

Insomnia

13%

Acute kidney injury

13%

Pharyngeal inflammation

13%

Pruritus

12%

Dysphonia

12%

Gamma-glutamyltransferase increased

11%

Pneumonia

11%

Dehydration

10%

Hyperthyroidism

10%

Hypoalbuminaemia

10%

Hypocalcaemia

10%

Headache

10%

Productive cough

Neck pain

Peripheral sensory neuropathy

Gastrooesophageal reflux disease

Hiccups

Hyperglycaemia

Hyperuricaemia

Dizziness

Hypophosphataemia

Urinary tract infection

Ear pain

Localised oedema

Hyperkalaemia

Erythema

Oral pain

Abdominal pain upper

Arthralgia

Anxiety

Febrile neutropenia

Dyspepsia

Saliva altered

Back pain

Oedema peripheral

Hypertension

Dyspnoea

Nasopharyngitis

Alopecia

Dry skin

Sepsis

Pneumonia aspiration

Trismus

Pneumonitis

Laryngeal oedema

Malnutrition

Pharyngeal haemorrhage

Cellulitis

Septic shock

Systemic infection

Clostridium difficile colitis

Cardiac arrest

Death

Bronchitis

Hepatitis

Immune-mediated hepatitis

Oesophagitis

General physical health deterioration

Hypophagia

Tumour haemorrhage

Cerebrovascular accident

Syncope

Acute respiratory failure

Aspiration

Colitis

Mouth haemorrhage

Hypersensitivity

Acute myocardial infarction

Abscess neck

Device related infection

Stoma site infection

Vascular device infection

Wound infection

Hypercalcaemia

Pulmonary embolism

Respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Pembrolizumab + CRT Followed by Pembrolizumab

Placebo + CRT Followed by Placebo

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Cohort 2 (Surgical Cohort): Arm B - Pembrolizumab monotherapyExperimental Treatment1 Intervention

Cohort 2 participants will be randomized into either group a or b (1:1): Group B participants will receive pembrolizumab monotherapy before and after surgery. * Pembrolizumab Before Surgery: Day 1 of the pre-surgical treatment cycle. * Pembrolizumab After Surgery: Day 1 of every other 21-day cycle (once every 6 weeks).

Group II: Cohort 2 (Surgical Cohort): Arm A - Pembrolizumab plus olaparib and temozolomideExperimental Treatment3 Interventions

Cohort 2 participants will be randomized into either group a or b (1:1): Group A participants will receive pembrolizumab, olaparib, and temozolomide before and after surgery. * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).

Group III: Cohort 1 (Safety Lead In): pembrolizumab plus olaparib and temozolomideExperimental Treatment3 Interventions

Following a 3 + 3 dose escalation design 6-18 participants will receive: * Olaparib 2x daily on Days 1-7 of each 21-day study cycle. * Temozolomide 1x daily on Days 1-7 of each 21-day study cycle. * Pembrolizumab on Day 1 of every other 21-day cycle (once every 6 weeks).

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Pembrolizumab

2017

Completed Phase 3

~3130

Temozolomide

2010

Completed Phase 3

~1880

Olaparib

2007

Completed Phase 4

~2190

0 / 39Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Pembrolizumab, a PD-1 inhibitor, enhances the immune system's ability to attack tumor cells by blocking the PD-1 pathway, which cancer cells use to evade immune detection. Olaparib, a PARP inhibitor, prevents cancer cells from repairing their DNA, leading to cell death, especially in cells with existing DNA repair deficiencies. Temozolomide, an alkylating agent, damages the DNA of cancer cells, preventing their replication and leading to cell death. These treatments are significant for Glioblastoma patients as they target the cancer cells' growth and survival mechanisms, potentially improving outcomes in this aggressive and challenging disease.