Brain Cancer
Conditions
Keywords
Brain Tumor
Brief summary
This research study is studying an immunotherapy as a possible treatment for Glioblastoma.
Detailed description
PD-1 works to help tumor cells continue to grow and multiply. Pembrolizumab (MK-3475) is a humanized monoclonal antibody. Humanized monoclonal is an antibody that is designed to block the action of the receptor, PD-1. The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for Glioblastoma but it has been approved for other uses.
Interventions
DRUGMK-3475
Sponsors
Dana-Farber Cancer Institute
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made. * Be willing and able to provide written informed consent/assent for the trial. * Be 18 years of age on day of signing informed consent. * Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A). * Previous first line therapy with at least radiotherapy. * Be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse. * Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan. * Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 14 days of registration. Table 1 Adequate Organ Function Laboratory Values * System Laboratory Value * Hematological * Absolute neutrophil count (ANC) ≥1,500 /mcL * Platelets ≥100,000 / mcL * Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) * Renal * Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN Hepatic * Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels \> 1.5 institutional ULN * AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN for subjects with Gilberts syndrome * Albumin \>2.5 mg/dL * Coagulation * International Normalized Ratio (INR) or Prothrombin Time (PT) * Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Creatinine clearance should be calculated per institutional standard. * CT or MRI within 14 days prior of registration. * An interval of at least 4 weeks (to registration) between prior surgical resection or one week for stereotactic biopsy. * An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression. * Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide). * From registration, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies (including vaccines). No wash-out period required from TTF. * Participants must have sufficient tissue from prior surgery revealing glioblastoma or variants for submission following registration. The following amount of tissue is required: * 1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR * 10 FFPE unstained slides (5 μm thick) * Patients must be undergoing surgery that is clinically indicated as determined by their care providers. Patients must be eligible for surgical resection with the expectation that the surgeon is able to resect at least 400mg of tumor with low risk of inducing neurological injury. * Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. * Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must agree to use highly effective contraception during study treatment and for 120 days after study discontinuation. Highly effective contraception is defined as either: * True Abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (as described in item 3.1.16 above). * Male Partner Sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner must be the sole partner for that participant. * Use of a combination of any two of the following: * Placement of an intrauterine device (IUD) or intrauterine system (IUS) * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular agents) * Male subjects must agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy.
Exclusion criteria
* Current or planned participation in a study of an investigational agent or using an investigational device. * Has a diagnosis of immunodeficiency. * Has tumor primarily localized to the brainstem or spinal cord. * Has presence of diffuse leptomeningeal disease or extracranial disease. * Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six months of registration. * Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc). * Requires treatment with high dose systemic corticosteroids defined as dexamethasone \> 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration. * Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery. * Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration. * Has a known history of active TB (Bacillus Tuberculosis). * Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade \> 3 within 6 months of registration. * Has a known additional malignancy that is progressing or requires active treatment within 3 years of registration. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Has known history of, or any evidence of active non-infectious pneumonitis. * Has an active infection requiring systemic therapy. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Examples include but are not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Has 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). * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days prior to registration. * Has a known hypersensitivity to any of the study therapy products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Infiltrating T Lymphocyte (TIL) Density | 2 weeks. TIL density is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1. | To measure changes in tumor infiltrating T lymphocyte (TIL) density, defined as % total cells. It will be assessed using pooled Group A and Group B patients. |
| Cell Cycle and Cancer Proliferation Genetic Signature | 2 weeks. Cell cycle/cancer proliferation genetic signature is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1. | To measure changes in cell cycle and cancer proliferation genetic signature; these results are reported using Gene Set Variation Analysis (GSVA) absolute enrichment scores (ES). GSVA scores are unit-less scores derived by comparing mRNA expression of a specific gene set to genes outside of the gene set in a sample. In this case, GSVA scores for "Farmers\_breast\_cancer\_cluster\_2, as previously described" were utilized. PMID 30742122 (https://pubmed.ncbi.nlm.nih.gov/30742122/) and PMID 23323831 (https://pubmed.ncbi.nlm.nih.gov/23323831/) It will be assessed using pooled Group A and Group B patients. |
| Incidence of Treatment-Emergent Adverse Events | 5 years. Although there is still 1 patient on active study treatment as of today (4/1/2024), we stopped looking at this information as of 6/2/2022 for study reporting purposes. | Number of Participants who Experienced a Serious Adverse Event (SAE) or Event of Clinical Interest (ECI) Deemed At Least Possibly Related to Pembrolizumab (MK3475). The following are measured as part of safety: laboratory safety assessments, KPS status, vital signs and physical examinations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 180 Days | To determine the efficacy of pembrolizumab in patients with surgically accessible recurrent/progressive glioblastoma (GBM) participants as measured by 6-month progression-free survival (PFS6) using Radiologic Assessment in Neuro-Oncology (RANO) criteria. Progression is defined using RANO criteria, as any of the following: 1. ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement, on stable or increasing doses of corticosteroids 2. Any new enhancing measurable lesion 3. Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose 4. Or failure to return for evaluation as a result of death or deteriorating condition |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPatrick Wen, MD
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A (Stage 1): Neoadjuvant + Adjuvant MK3475 * Single dose of Pembrolizumab (MK3475) @ 200 mg IV
* Surgery within 14 days (+/- 5 days) of Neoadjuvant dose
* Adjuvant Pembrolizumab (MK3475) @ 200 mg IV every 3 weeks to start upon recovery from surgery (and no more than 35 days after surgery) until disease progression or unacceptable toxicity.
* Pembrolizumab (MK-3475) administered intravenously over 30 minutes (-5 min/+10 min) | 16 |
| Group A Expansion Cohort (Stage 2): Neoadjuvant + Adjuvant MK3475 * Single dose of Pembrolizumab (MK3475) @ 200 mg IV
* Surgery within 14 days (+/- 5 days) of Neoadjuvant dose
* Adjuvant Pembrolizumab (MK3475) @ 200 mg IV every 3 weeks to start upon recovery from surgery (and no more than 35 days after surgery) until disease progression or unacceptable toxicity.
* Pembrolizumab (MK-3475) administered intravenously over 30 minutes (-5 min/+10 min) | 25 |
| Group B (Stage 1): Adjuvant MK3475 * Surgery (NO pre-surgical drug)
* Adjuvant Pembrolizumab (MK3475) @ 200 mg IV every 3 weeks to start upon recovery from surgery (and no more than 35 days after surgery) until disease progression or unacceptable toxicity.
* Pembrolizumab (MK-3475) administered intravenously over 30 minutes (-5 min/+10 min) | 16 |
| Total | 57 |
Baseline characteristics
| Characteristic | Group A Expansion Cohort (Stage 2): Neoadjuvant + Adjuvant MK3475 | Group B (Stage 1): Adjuvant MK3475 | Group A (Stage 1): Neoadjuvant + Adjuvant MK3475 | Total |
|---|---|---|---|---|
| Age, Customized 21-29 years old | 1 years | 0 years | 1 years | 2 years |
| Age, Customized 30-39 years old | 2 years | 2 years | 2 years | 6 years |
| Age, Customized 40-49 years old | 6 years | 0 years | 1 years | 7 years |
| Age, Customized 50-59 years old | 3 years | 5 years | 3 years | 11 years |
| Age, Customized 60-69 years old | 10 years | 6 years | 9 years | 25 years |
| Age, Customized 70 + | 3 years | 3 years | 0 years | 6 years |
| Baseline Karnofsky Performance Status (KPS) KPS = 100 | 0 participants | 0 participants | 1 participants | 1 participants |
| Baseline Karnofsky Performance Status (KPS) KPS = 70 | 2 participants | 1 participants | 5 participants | 8 participants |
| Baseline Karnofsky Performance Status (KPS) KPS = 80 | 9 participants | 4 participants | 7 participants | 20 participants |
| Baseline Karnofsky Performance Status (KPS) KPS = 90 | 14 participants | 11 participants | 3 participants | 28 participants |
| Current Relapse # 1st Relapse | 24 Participants | 15 Participants | 12 Participants | 51 Participants |
| Current Relapse # 2nd Relapse | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 13 Participants | 13 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| IDH1/2 Mutation Status Negative | 24 Participants | 13 Participants | 12 Participants | 49 Participants |
| IDH1/2 Mutation Status Positive | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| IDH1/2 Mutation Status Unknown | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| MGMT Methylation Status MGMT Methylated | 12 Participants | 11 Participants | 6 Participants | 29 Participants |
| MGMT Methylation Status MGMT Unmethylated | 11 Participants | 4 Participants | 7 Participants | 22 Participants |
| MGMT Methylation Status Unknown | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 1 Participants | 9 Participants |
| Race (NIH/OMB) White | 18 Participants | 12 Participants | 15 Participants | 45 Participants |
| Region of Enrollment United States | 25 participants | 16 participants | 16 participants | 57 participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 17 Participants | 5 Participants | 9 Participants | 31 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 0 mg/day | 20 Participants | 9 Participants | 9 Participants | 38 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 1 mg/day | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 2 mg/day | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 3 mg/day | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 4 mg/day | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Total Daily Steroid Dose at Registration (mg/day) 6 mg/day | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 37 / 41 | 16 / 16 |
| other Total, other adverse events | 40 / 41 | 16 / 16 |
| serious Total, serious adverse events | 18 / 41 | 9 / 16 |
Outcome results
Primary
Cell Cycle and Cancer Proliferation Genetic Signature
To measure changes in cell cycle and cancer proliferation genetic signature; these results are reported using Gene Set Variation Analysis (GSVA) absolute enrichment scores (ES). GSVA scores are unit-less scores derived by comparing mRNA expression of a specific gene set to genes outside of the gene set in a sample. In this case, GSVA scores for Farmers\_breast\_cancer\_cluster\_2, as previously described were utilized. PMID 30742122 (https://pubmed.ncbi.nlm.nih.gov/30742122/) and PMID 23323831 (https://pubmed.ncbi.nlm.nih.gov/23323831/) It will be assessed using pooled Group A and Group B patients.
Time frame: 2 weeks. Cell cycle/cancer proliferation genetic signature is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1.
Population: Group A = Initial Group A Cohort (Stage 1) + Group A Expansion Cohort (Stage 2) Group B = Initial Group B Cohort (Stage 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Neoadjuvant + Adjuvant MK3475 (Stage 1 Cohort + Stage 2 Expansion Cohort) | Cell Cycle and Cancer Proliferation Genetic Signature | -0.1758 unitless | Standard Error 0.08192 |
| Group B: Adjuvant MK3475 (Stage 1 Cohort) | Cell Cycle and Cancer Proliferation Genetic Signature | 0.3008 unitless | Standard Error 0.1472 |
Primary
Incidence of Treatment-Emergent Adverse Events
Number of Participants who Experienced a Serious Adverse Event (SAE) or Event of Clinical Interest (ECI) Deemed At Least Possibly Related to Pembrolizumab (MK3475). The following are measured as part of safety: laboratory safety assessments, KPS status, vital signs and physical examinations.
Time frame: 5 years. Although there is still 1 patient on active study treatment as of today (4/1/2024), we stopped looking at this information as of 6/2/2022 for study reporting purposes.
Population: All patients who received at least one dose of pembrolizumab on study are included in this analysis.~Group A = Initial Group A Cohort (Stage 1) + Group A Expansion Cohort (Stage 2) Group B = Initial Group B Cohort (Stage 1)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Neoadjuvant + Adjuvant MK3475 (Stage 1 Cohort + Stage 2 Expansion Cohort) | Incidence of Treatment-Emergent Adverse Events | Patients Experiencing an SAE Deemed At Least Possibly Related to Pembrolizumab | 13 Participants |
| Group A: Neoadjuvant + Adjuvant MK3475 (Stage 1 Cohort + Stage 2 Expansion Cohort) | Incidence of Treatment-Emergent Adverse Events | Patients Experiencing an ECI Deemed At Least Possibly Related to Pembrolizumab | 0 Participants |
| Group B: Adjuvant MK3475 (Stage 1 Cohort) | Incidence of Treatment-Emergent Adverse Events | Patients Experiencing an SAE Deemed At Least Possibly Related to Pembrolizumab | 5 Participants |
| Group B: Adjuvant MK3475 (Stage 1 Cohort) | Incidence of Treatment-Emergent Adverse Events | Patients Experiencing an ECI Deemed At Least Possibly Related to Pembrolizumab | 0 Participants |
Primary
Tumor Infiltrating T Lymphocyte (TIL) Density
To measure changes in tumor infiltrating T lymphocyte (TIL) density, defined as % total cells. It will be assessed using pooled Group A and Group B patients.
Time frame: 2 weeks. TIL density is determined in surgical tumor tissue; on-study surgery occurs 14 days (+/- 5 days) after Neoadjuvant Day 1.
Population: Group A = Initial Group A Cohort (Stage 1) + Group A Expansion Cohort (Stage 2) Group B = Initial Group B Cohort (Stage 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Neoadjuvant + Adjuvant MK3475 (Stage 1 Cohort + Stage 2 Expansion Cohort) | Tumor Infiltrating T Lymphocyte (TIL) Density | 2.2 percentage of total stromal area | Standard Error 0.32 |
| Group B: Adjuvant MK3475 (Stage 1 Cohort) | Tumor Infiltrating T Lymphocyte (TIL) Density | 2.1 percentage of total stromal area | Standard Error 0.63 |
Secondary
Progression Free Survival (PFS)
To determine the efficacy of pembrolizumab in patients with surgically accessible recurrent/progressive glioblastoma (GBM) participants as measured by 6-month progression-free survival (PFS6) using Radiologic Assessment in Neuro-Oncology (RANO) criteria. Progression is defined using RANO criteria, as any of the following: 1. ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement, on stable or increasing doses of corticosteroids 2. Any new enhancing measurable lesion 3. Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose 4. Or failure to return for evaluation as a result of death or deteriorating condition
Time frame: 180 Days
Population: Censoring \& Final PFS #s:~• Group A patients censored from PFS Analysis:~o 1 patient's on study surgery did not show recurrent disease (53)~Group A = Initial Stage 1 Cohort + Stage 2 Expansion Cohort Group B = Initial Stage 1 Cohort~* 1 patient's histology did not confirm diagnosis of GBM (28)~* 3 patients' disease was considered unevaluable (47, 49, \& 60)~ • Group B patients censored from PFS Analysis:~* 1 patient's on study surgery did not show recurrent disease (13)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Neoadjuvant + Adjuvant MK3475 (Stage 1 Cohort + Stage 2 Expansion Cohort) | Progression Free Survival (PFS) | 5 Participants |
| Group B: Adjuvant MK3475 (Stage 1 Cohort) | Progression Free Survival (PFS) | 2 Participants |