NCT02794883

Tremelimumab and Durvalumab in Combination or Alone in Treating Patients With Recurrent Malignant Glioma

Completed Phase 2 Results posted Last updated 18 April 2022

What this trial tests

Phase 2 trial testing Durvalumab in Malignant Glioma in 36 participants. Completed in 17 June 2020.

Timeline

1 November 2016

Primary endpoint
9 May 2018

17 June 2020

Quick facts

Lead sponsor	Northwestern University
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	36
Start date	1 November 2016
Primary completion	9 May 2018
Estimated completion	17 June 2020
Sites	1 location across United States

Drugs / interventions tested

• Durvalumab — full drug profile →
• Laboratory Biomarker Analysis — full drug profile →
• Surgical Procedure
• Tremelimumab (TREMELIMUMAB) — full drug profile →

Conditions studied

• Malignant Glioma — all drugs for Malignant Glioma →
• Recurrent Glioblastoma — all drugs for Recurrent Glioblastoma →

Sponsor

Northwestern University

Who can join

18 and older, any sex, with Malignant Glioma or Recurrent Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

MRI Changes Secondary · Baseline and 3 days after surgery

To assess MRI changes in lesion size in patients treated with either Tremelimumab or MEDI4736 alone and in combination of both post surgery. Only patients who have been administered at least one dose of investigational drug, undergone surgery, and have undergone at least one post-surgery disease assessment will be evaluable for this endpoint. Changes will be summarized using means. MRI changes below show the changes from baseline to after surgery.

Group	Value	95% CI
Arm 1: Tremelimumab Only	1410	± 4290
Arm 2: MEDI4736 Only	1720	± 2730
Arm 3: Tremelimumab + MEDI4736	3020	± 7320

Number of Patients Adverse Events Regardless of Attribution to the Study Drug Graded 3, 4, and 5 Secondary · From baseline, pre-surgery treatment period (2 weeks prior to surgery), and post-surgery treatement, where the range of cycles attempted post-surgery was 0-16 (1 Cycle = 4 weeks), to 90 days post treatment discontinuation

Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs graded 3, 4, 5 (regardless of attribution to the study drug) are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threa

Grade 5 Disease Progression

Group	Value	95% CI
Arm 1: Tremelimumab Only	5
Arm 2: MEDI4736 Only	4
Arm 3: Tremelimumab + MEDI4736	2

Grade 3 Left-sided Weakness

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	1

Grade 3 UTI

Group	Value	95% CI
Arm 1: Tremelimumab Only	2
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	1

Grade 3 Pulmonary Embolism

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	0

Grade 3 Fall

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	0

Grade 5 Intracranial hemorrhage

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	0

Grade 4 Encephalopathy

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	1
Arm 3: Tremelimumab + MEDI4736	0

Grade 4 Seizures

Group	Value	95% CI
Arm 1: Tremelimumab Only	1
Arm 2: MEDI4736 Only	0
Arm 3: Tremelimumab + MEDI4736	0

Overall Survival Secondary · From the start of treatment (pre-surgery treatment period = 2 weeks), to surgery, to post-surgery treatment, where range of cycles attempted was 0-16 (1 Cycle = 4 weeks), to 2 years post treatment discontinuation

To determine post-surgery the overall survival for patients treated with Tremelimumab or MEDI4736 alone and in combination. This will be defined as the number of months surviving from the time of first dose of study treatment until death by any cause. Only patients who have been administered at least one dose of investigational drug and undergone surgery will be evaluable for this endpoint.

Group	Value	95% CI
Arm 1: Tremelimumab Only	7.246	2.746 – 16.32
Arm 2: MEDI4736 Only	11.71	8.332 – 32.71
Arm 3: Tremelimumab + MEDI4736	7.703	7.411 – 40.14

Time to Progression Secondary · From start of treatment (pre-surgery treatment period = 2 weeks), to surgery, to post-surgery treatment where range of cycles attempted was 0-16 (1 Cycle = 4 weeks), and up to 2 years of follow-up after treatment discontinuation

To the time to progression (per Modified RANO criteria and iRANO criteria) for patients treated with either Tremelimumab or MEDI4736 alone and in combination. This will be defined as the number of months from the time of first dose of study treatment until progression of disease (PD) or death from any cause. Only patients who have been administered at least one dose of investigational drug and undergone surgery will be evaluable for this endpoint. Definition of PD per RANO criteria: New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticost

Group	Value	95% CI
Arm 1: Tremelimumab Only	2.746	2.68 – 8.727
Arm 2: MEDI4736 Only	4.356	2.941 – 32.74
Arm 3: Tremelimumab + MEDI4736	4.913	2.905 – 120.4

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) were collected over a 3 year period. For other AEs ,each patient was followed from the time of treatment, during treatment at the beginning of each cycle through 90 days post last treatment. For Serious AEs, each patient was followed at time of consent and 90 days post last treatment. Patients received a single dose of study treatment pre-surgery. The range of adjuvant/post-surgery cycles attempted was 0-16 (1 cycle = 4 weeks).. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Arm 1: Tremelimumab Only

Serious: 9/12 (75%)

Deaths: 12/12

Arm 2: MEDI4736 Only

Serious: 10/12 (83%)

Deaths: 10/11

Arm 3: Tremelimumab + MEDI4736

Serious: 8/12 (67%)

Deaths: 10/11

Serious adverse events (23 terms)

Reaction	System	Arm 1: Tremelimumab Only	Arm 2: MEDI4736 Only	Arm 3: Tremelimumab + MEDI…
Disease Progression	General disorders	—	—	—
Seizures	Nervous system disorders	—	—	—
Encephalopathy	Nervous system disorders	—	—	—
Clinical decline	General disorders	—	—	—
Weakness	Nervous system disorders	—	—	—
Left-sided weakness	Nervous system disorders	—	—	—
Urinary tract infection	Renal and urinary disorders	—	—	—
Pulmonary embolism	Vascular disorders	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Intracranial hemorrhage	Nervous system disorders	—	—	—
Agitation	Psychiatric disorders	—	—	—
Mental status change	Nervous system disorders	—	—	—
Viral meningitis	Infections and infestations	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Intraparenchymal hemorrhage	Nervous system disorders	—	—	—
Hydrocephalus	Nervous system disorders	—	—	—
Gait imbalance	General disorders	—	—	—
Nausea/Vomiting	Gastrointestinal disorders	—	—	—
Colitis	Gastrointestinal disorders	—	—	—
Sepsis	Infections and infestations	—	—	—
Wound infection	Infections and infestations	—	—	—
Stroke	Nervous system disorders	—	—	—
Wound dehiscence	Injury, poisoning and procedural complications	—	—	—

Other adverse events (167 terms — click to expand)

Reaction	System	Arm 1: Tremelimumab Only	Arm 2: MEDI4736 Only	Arm 3: Tremelimumab + MEDI…
Hyperglycemia	Metabolism and nutrition disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—
Lymphocyte count decreased	Investigations	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—
Fatigue	General disorders	—	—	—
Platelet count decreased	Investigations	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—
Hypomagnesemia	Metabolism and nutrition disorders	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—
Ataxia	Nervous system disorders	—	—	—
Confusion	Psychiatric disorders	—	—	—
Sinus bradycardia	Cardiac disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Fever	General disorders	—	—	—
Gait disturbance	General disorders	—	—	—
Weight loss	Investigations	—	—	—
White blood cell decreased	Investigations	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—
Memory impairment	Nervous system disorders	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—
Pain	General disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Weight gain	Investigations	—	—	—
Hypernatremia	Metabolism and nutrition disorders	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—
Cognitive disturbance	Nervous system disorders	—	—	—
Facial muscle weakness	Nervous system disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Urinary frequency	Renal and urinary disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash acneiform	Skin and subcutaneous tissue disorders	—	—	—
Thromboembolic event	Vascular disorders	—	—	—
Blood and lymphatic disorders NOS	Blood and lymphatic system disorders	—	—	—

Most-reported serious reactions: Disease Progression, Seizures, Encephalopathy, Clinical decline, Weakness, Left-sided weakness, Urinary tract infection, Pulmonary embolism.

Data from ClinicalTrials.gov NCT02794883 adverse events section.

Sponsor's own description

The main purpose of this trial is to investigate the effects of a new class of drugs that help the patient's immune system attack their tumor (glioblastoma multiforme - GBM). These drugs have already shown benefit in some other cancer types and are now being explored in GBM. Both tremelimumab and durvalumab (MEDI4736) are "investigational" drugs, which means that the drugs are not approved by the Food and Drug Administration (FDA). Both drugs are antibodies (proteins used by the immune system to fight infections and cancers). Durvalumab attaches to a protein in tumors called PD-L1. It may prevent cancer growth by helping certain blood cells of the immune system get rid of the tumor. Tremelimumab stimulates (wakes up) the immune system to attack the tumor by inhibiting a protein molecule called CTLA-4 on immune cells. Combining the actions of these drugs may result in better treatment options for patients with glioblastoma.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet.
   Filley AC, Henriquez M, Dey M. · · 2017 · cited 284× · PMID 29207684 · DOI 10.18632/oncotarget.21586
2. Current State of Immunotherapy for Treatment of Glioblastoma.
   McGranahan T, Therkelsen KE, Ahmad S, Nagpal S. · · 2019 · cited 209× · PMID 30790064 · DOI 10.1007/s11864-019-0619-4
3. Tumor microenvironment signaling and therapeutics in cancer progression.
   Goenka A, Khan F, Verma B, Sinha P, et al · · 2023 · cited 203× · PMID 37005490 · DOI 10.1002/cac2.12416
4. Immunotherapy: a promising approach for glioma treatment.
   Yasinjan F, Xing Y, Geng H, Guo R, et al · · 2023 · cited 156× · PMID 37744349 · DOI 10.3389/fimmu.2023.1255611
5. PD-L1/PD-1 Axis in Glioblastoma Multiforme.
   Litak J, Mazurek M, Grochowski C, Kamieniak P, et al · · 2019 · cited 152× · PMID 31661771 · DOI 10.3390/ijms20215347
6. Advances in Glioblastoma Therapy: An Update on Current Approaches.
   Angom RS, Nakka NMR, Bhattacharya S. · · 2023 · cited 140× · PMID 38002496 · DOI 10.3390/brainsci13111536
7. PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?
   Khasraw M, Reardon DA, Weller M, Sampson JH. · · 2020 · cited 110× · PMID 32527943 · DOI 10.1158/1078-0432.ccr-20-1135
8. Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.
   McBain C, Lawrie TA, Rogozińska E, Kernohan A, et al · · 2021 · cited 105× · PMID 34559423 · DOI 10.1002/14651858.cd013579.pub2