Combination Immunotherapy Treatment for Glioblastoma Including BreakVax ImmunoTreatment (Designed and Manufactured Per Patient), Chemotherapy and Anti PD-1 Therapy

BreakBio Corp

Status and phase

Begins enrollment this month

Phase 2

Phase 1

Conditions

Glioblastoma (GBM)

Treatments

Drug: Temozolomide (TMZ)

Drug: Ipilimumab 2.5 mg

Drug: BreakVax

Drug: Pembrolizumab

Drug: Losartan and aspirin

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT07762716

BreakBio-3 Substudy B

Details and patient eligibility

About

The objective of this study is to evaluate the safety, feasibility, and preliminary antitumor activity of this multi-component immunotherapy strategy in patients with advanced solid tumors. The study is designed to assess whether coordinated enhancement of antigen-specific T-cell priming and tumor microenvironment modulation can improve immune-mediated tumor control.

In this study, BreakVax with adjuvants (Montanide and Poly-ICLC) is administered in combination with:

Low-dose subcutaneous ipilimumab at the injection site as a dendritic cell adjuvant to enhance local dendritic cell-mediated T-cell priming;
Pembrolizumab to mitigate PD-1-mediated T-cell exhaustion and sustain effector function;
Standard-of-care chemotherapy, which may promote immunogenic cell death, increase antigen release and modulate the tumor microenvironment; and
Losartan and aspirin, which have been associated in preclinical and translational studies with modulation of stromal architecture, vascular normalization, and reduction of tumor-associated immunosuppressive signaling.

This is a Phase 1/2, multi-center, open-label single-arm clinical study in adult patients who have Glioblastoma (GBM).

The study consists of two components: a Safety Lead-in Cohort and a combination therapy cohort. The Safety Lead-in Cohort is designed to evaluate safety and tolerability of the study combination and to characterize dose-limiting toxicities (DLTs). The combination therapy cohort portion intends to evaluate the superiority of the study combination treatment vs the SOC chemotherapy, measured by OS at 12 months

Enrollment

10 estimated patients

Sex

All

Ages

18 to 72 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age ≥ 18 years and < 72
Patients with histologically confirmed GBM who have sent 200 mg (approximately) of tumor tissue (fresh tissue immersed in AllProtect then frozen) to BreakBio for analysis.
KPS of 80 or greater on day of first dose
Patient has adequate organ function on day one of the trial as defined by:
- Neutrophil to Lymphocyte Ratio (NLR)1 at a healthy adult's normal level: ≤ 3.5
- Absolute Neutrophil Count (ANC) at the normal level: ≤ 7,000/mm3
- Absolute Lymphocyte Count in normal level: ≥ 1,000/mm3
- Monocytes at normal level: < 700/mm3
- Platelet count: ≥ 100 x 109/L (without transfusion support in the last two weeks)
- Hemoglobin: > 10.0 g/dL (without transfusion support in the last two weeks)
- AST and ALT: ≤ 3 X institutional upper limit of normal (ULN) in the absence of liver mets; AST and/or ALT may be ≤ 5 x ULN in the setting of liver metastases
- Total Bilirubin at the normal level: ≤ 1.2mg/dL
- Serum creatinine: ≤ 1.5 x institution's ULN
- Albumin at the normal level: ≥ 3.4 g/dL
- Serum Magnesium at normal level: ≥ 1.7 mg/dL
- Pulse oximetry ≥ 92% on room air.
Provision of consent for on-treatment biopsy (compulsory) and post-treatment biopsy (optional).
Both male and female patients enrolled in this trial must agree to use effective contraception during the course of the trial and for at least 3 months after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
Negative pregnancy test ≤ 7 days prior to day one of cycle 1, for women of childbearing potential only.
Life expectancy > 6 months.
Willing and able to provide informed consent

Exclusion criteria

Prior exposure to anti PD- 1/PD-L1 agents.
Prior exposure to immunosuppressive therapy within the last 12 months prior to enrollment.
Receiving or previously receiving oral or IV steroids within 6 weeks of starting study treatment. Currently using or previously used topical steroids within 6 weeks of starting study treatment. Expected to require steroid-containing pre-meds before chemotherapy doses.
Patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) phenotype
Any liver metastasis greater than 2 cm or greater than 5 liver metastases. Patients who have liver metastasis removed by surgery, and therefore meet this criterion at first dose, may enroll.
Patients not recovered from all clinically significant toxic effects of previous therapies to ≤Grade 1 or baseline with the exception of peripheral neuropathy and alopecia.
Patients not recovered adequately from the toxicity and/or complications from any major surgery prior to starting study treatment.
Known or suspected hypersensitivity to any of the study drugs.
Received an investigational agent within 28 days prior to the first dose of study drug.
History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
LVEF <50%.
Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. Individuals who are hepatitis C antibody positive may be enrolled if negative viral load confirmed.
History of autoimmune disease including inflammatory bowel disease (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener's granulomatosis); central nervous system or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré syndrome, myasthenia gravis, multiple sclerosis). Individuals with vitiligo, Sjogren's Syndrome, interstitial cystitis, Graves' or Hashimoto's Disease, celiac disease, DM1, hypothyroidism stable on hormone replacement, or any autoimmune disease without symptoms and not requiring active therapy for at least 2 years will be allowed with Study Medical Monitor's approval.
A serious local infection (e.g. cellulitis, abscess) or systemic infection (e.g. pneumonia, septicemia) which requires systemic antibiotic treatment within 4 weeks prior to the first dose of study medication.
Receiving coumarin-derived anticoagulants.
Unable or unwilling to withhold or discontinue any prohibited or restricted medications/procedures for the specified windows during the study.
Inability or refusal to comply with the protocol or with the clinical trial procedures.
If female, pregnant or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
Chronic intake of drugs that lead to known interference with metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Wort /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (Note: participants in this study should avoid consuming grapefruit or grapefruit-containing products during the duration of the study, including the screening phase, treatment period, and follow-up period).
Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen
Any hemorrhage or bleeding event ≥ National Cancer Institute - Common terminology criteria for adverse events (NCI-CTCAE) Grade 3 within 28 days prior to the start of study medication
History of other invasive cancer within 2 years prior to enrollment, except for treated non-melanoma skin cancer
Known DNA Polymerase Epsilon (POLE) mutations

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

10 participants in 1 patient group

BreakVax Arm

Experimental group

Description:

A cycle for this study is defined as 28 days. BreakVax along with adjuvants and low-dose subcutaneous ipilimumab (as an adjuvant) will be administered on Day 1 and D15 of Cycle 1, and will then be administered on D1 of every cycle thereafter until disease progression per RANO criteria. In addition to BreakVax, patients in the BreakVax Arm will receive losartan daily and temozolomide - without steroid pre-medications (see disallowed concomitant treatment below). Patients will receive aspirin QD except the day BreakVax is administered and the 2 following days in cycles in which the patient is receiving BreakVax. Patients will begin pembrolizumab on Day 21 of Cycle 2 and it will then be administered every 6 weeks thereafter

Treatment:

Drug: Losartan and aspirin

Drug: Pembrolizumab

Drug: BreakVax

Drug: Ipilimumab 2.5 mg

Drug: Temozolomide (TMZ)

Trial contacts and locations

Data sourced from clinicaltrials.gov

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