NCT02313272

Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas

Completed Phase 1 Results posted Last updated 23 October 2023

What this trial tests

Phase 1 trial testing Hypofractionated Stereotactic Irradiation (HFSRT) in Malignant Glioma in 32 participants. Completed in 9 August 2021.

Timeline

28 July 2015

Primary endpoint
13 September 2018

9 August 2021

Quick facts

Lead sponsor	H. Lee Moffitt Cancer Center and Research Institute
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	32
Start date	28 July 2015
Primary completion	13 September 2018
Estimated completion	9 August 2021
Sites	1 location across United States

Drugs / interventions tested

• Hypofractionated Stereotactic Irradiation (HFSRT)
• Pembrolizumab (pembrolizumab) — full drug profile →
• Bevacizumab (Bevacizumab-Bvzr) — full drug profile →

Conditions studied

• Malignant Glioma — all drugs for Malignant Glioma →

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Who can join

18 and older, any sex, with Malignant Glioma. 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.

Maximum Tolerated Dose (MTD) Primary · Up to 24 months

The pembrolizumab dose used in the dose expansion cohort will be MTD determined from the dose escalation phase. Dose Escalation: The maximum tolerated dose (MTD) is the highest dose of pembrolizumab in combination with bevacizumab after radiation therapy that does not cause unacceptable toxicity in more than one of six patients at that dose level. The MTD is defined as one dose level below the highest toxic dose (i.e., the Dose Limiting Toxicity (DLT) dose).

Group	Value	95% CI
HFSRT With Pembrolizumab and Bevacizumab	200

Response Rate (RR) Secondary · Up to 24 months

Response rate of pembrolizumab given in combination with bevacizumab and hypofractionated stereotactic re-irradiation of recurrent high grade gliomas. Response to treatment will be assessed by the investigator and according to the Response Assessment Criteria for High-Grade Gliomas (RANO Criteria). Brain MRI will be performed every 6 weeks beginning at the end of Week 6 (± 1 week) for 3 cycles and then every 12 weeks (± 1 week) until disease progression or treatment discontinuation, whichever occurs later.

Complete Response

Group	Value	95% CI
Dose Level 1: HFSRT With Pembrolizumab and Bevacizumab	33.33
Dose Level 2: HRSRT With Pembrolizumb and Bevacizumab	6.25
Participants Treated at Maximum Tolerated Dose	0

Partial Response

Group	Value	95% CI
Dose Level 1: HFSRT With Pembrolizumab and Bevacizumab	33.33
Dose Level 2: HRSRT With Pembrolizumb and Bevacizumab	62.5
Participants Treated at Maximum Tolerated Dose	71.88

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events recorded day 1 of study treatment through 30 days following cessation of treatment, 37 months in total.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Dose Level 1: HFSRT With Pembrolizumab and Bevacizumab

Serious: 3/3 (100%)

Deaths: 3/3

Dose Level 2: HRSRT With Pembrolizumb and Bevacizumab

Serious: 7/16 (44%)

Deaths: 14/16

Participants Treated at Maximum Tolerated Dose

Serious: 8/13 (62%)

Deaths: 10/13

Serious adverse events (43 terms)

Reaction	System	Dose Level 1: HFSRT With P…	Dose Level 2: HRSRT With P…	Participants Treated at Ma…
Neoplasms benign, malignant and unspecified -Other	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Wound infection	Infections and infestations	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—
Fever	General disorders	—	—	—
Surgical and medical procedures-Other	Surgical and medical procedures	—	—	—
Dysphasia	Nervous system disorders	—	—	—
Confusion	Psychiatric disorders	—	—	—
Thromboembolic event	Vascular disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Vomitting	Gastrointestinal disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—
Hypotension	Vascular disorders	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Muscle weakness, right sided	Musculoskeletal and connective tissue disorders	—	—	—
Nervous System disorders- Other	Nervous system disorders	—	—	—
Psychiatric disorders - Other	Psychiatric disorders	—	—	—
Suicide attempt	Psychiatric disorders	—	—	—
Lung infection	Infections and infestations	—	—	—
Sepsis	Infections and infestations	—	—	—
Urinary incontinence	Renal and urinary disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Non-cardiac chest pain	General disorders	—	—	—
Lung infection - pneumonia	Infections and infestations	—	—	—

Other adverse events (152 terms — click to expand)

Reaction	System	Dose Level 1: HFSRT With P…	Dose Level 2: HRSRT With P…	Participants Treated at Ma…
Lymphocyte count decreased	Investigations	—	—	—
Headache	Nervous system disorders	—	—	—
Confusion	Psychiatric disorders	—	—	—
Fatigue	General disorders	—	—	—
Hyperkalemia	Metabolism and nutrition disorders	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Pain	General disorders	—	—	—
Proteinuria	Renal and urinary disorders	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Gait disturbance	General disorders	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Platelet count decreased	Investigations	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Depression	Psychiatric disorders	—	—	—
Fever	General disorders	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Chills	General disorders	—	—	—
Creatinine increased	Investigations	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Dysphasia	Nervous system disorders	—	—	—
Edema limbs	General disorders	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—
Memory impairment	Nervous system disorders	—	—	—
Muscle weakness left-sided	Musculoskeletal and connective tissue disorders	—	—	—
Nervous system disorders - Other	Nervous system disorders	—	—	—
Paresthesia	Nervous system disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
White blood cell decreased	Investigations	—	—	—

Most-reported serious reactions: Neoplasms benign, malignant and unspecified -Other, Wound infection, Generalized muscle weakness, Fever, Surgical and medical procedures-Other, Dysphasia, Confusion, Thromboembolic event.

Data from ClinicalTrials.gov NCT02313272 adverse events section.

Sponsor's own description

The purpose of this study is to see if the addition of the investigation drug called pembrolizumab (Keytruda®) to radiation therapy and bevacizumab (Avastin®) is safe and can help with controlling the growth of tumors, in participants with recurrent high grade glioma.

Publications & conference data

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

1. Targetable genetic features of primary testicular and primary central nervous system lymphomas.
   Chapuy B, Roemer MG, Stewart C, Tan Y, et al · · 2016 · cited 420× · PMID 26702065 · DOI 10.1182/blood-2015-10-673236
2. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
   Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
3. Current clinical trials testing the combination of immunotherapy with radiotherapy.
   Kang J, Demaria S, Formenti S. · · 2016 · cited 293× · PMID 27660705 · DOI 10.1186/s40425-016-0156-7
4. 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
5. 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
6. Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data.
   Ott PA, Hodi FS, Buchbinder EI. · · 2015 · cited 184× · PMID 26442214 · DOI 10.3389/fonc.2015.00202
7. 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
8. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.
   Hendry SA, Farnsworth RH, Solomon B, Achen MG, et al · · 2016 · cited 150× · PMID 28066431 · DOI 10.3389/fimmu.2016.00621