A Phase II, Multi-center, Open-label Study of a Conditionally Replicative Adenovirus (DNX-2401) with Pembrolizumab (KEYTRUDA®) for Recurrent Glioblastoma or Gliosarcoma
Frederick F. Lang
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: DNX-2401,Pembrolizumab
Treatment Location: Both at MDACC & and Other Sites
Sponsor: DNAtrix; Inc.,Merck & Co.
Primary Objectives To evaluate the safety of escalating doses of DNX-2401 and the overall safety of the declared dose of intratumoral DNX-2401 when followed by sequential intravenous administration of pembrolizumab To determine the objective response rate (ORR) Secondary Objectives To determine 12-month overall survival (OS-12) To determine the clinical benefit rate (CBR defined as CR + PR + SD) per RANO criteria and RANO criteria modified to account for pseudo-progression (e.g., iRANO) Exploratory Objectives To evaluate overall survival (OS), OS-8, progression free survival (PFS), progression free survival at six months (PFS-6), time to tumor response, duration of response, per RANO criteria and RANO criteria modified to account for pseudo-progression (e.g., iRANO) To evaluate changes in Karnofsky performance status (KPS) and neurologic status To evaluate cytokines, lymphocyte sub-types and other potential biomarkers (e.g., PD-1, PD-L1 expression, genetic mutation)
IRB Review and Approval Date: 03/09/2017
Recruitment Status: Open
Projected Accrual: 48
1) >/= 18 years of age on the day of informed consent
2) A single glioblastoma or gliosarcoma tumor with histopathological confirmation. (Notes: If a prior diagnosis exists such as anaplastic astrocytoma, or other tumor types that have progressed to GBM, inclusion may be allowed following discussion with the DNAtrix Medical Monitor or designee. Subjects with contiguous tumors may be eligible with the approval of DNAtrix prior to the initiation of further screening activities.)
3) First or presenting second recurrence of glioblastoma or gliosarcoma at time of consent
4) Gross total or partial tumor resection, including tumor debulking, is not possible or planned
5) A single measurable tumor that is at least 10.0 mm longest diameter (LDi) x 10.0 mm shortest diameter (SDi) and this tumor does not exceed 40.0 mm in LDi or SDi
6) The measurable area of the tumor is solid/nodular and is not cystic (Note: Most tumors will have cystic components and subjects who have a tumor that is partially cystic may be eligible for the study with the approval of the DNAtrix Medical Monitor or designee if the Principal Investigator/Neurosurgeon can perform an injection within the measurable solid parts of the tumor.)
7) Willing to provide a tumor tissue sample for biomarker analysis and mutational status from an archived slide or newly obtained stereotactic core biopsy
8) Tumors must be accessible for stereotactic injection
9) Confirmatory evidence of tumor recurrence (e.g., progression after last treatment) on the screening MRI 15 days to minus 72 hours, inclusive, prior to planned start time of DNX-2401 administration
10) Tumor wherein the location will not risk delivery of DNX-2401 into the ventricular system
11) Tumor recurrence or progression after previously failing surgical resection, chemotherapy or radiation
12) Resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except neuropathy and alopecia). (Note: Subjects with </= Grade 2 neuropathy and/or alopecia are an exception to this criterion and they will not be excluded for these reasons alone.)
13) Adequate hematological function: Absolute neutrophil count (ANC) >/= 1,500/mcL; WBC >/= 2.5 x 103/mm3; Platelets: >/= 100,000/mcL; Hemoglobin >/= 10 g/dL or >/= 5.6 mmol/L
14) Adequate renal function: Creatinine </= 1.5x ULN; BUN </= 1.5x ULN
15) Adequate hepatic function: Total bilirubin </= 1.5 x ULN or Direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5x ULN; AST (SGOT) and ALT (SGPT) </= 2.5x ULN
16) Adequate coagulation: International Normalized Ratio (INR) </= 1.5x ULN; Prothrombin Time (PT) </= 1.5x ULN; Activated Partial Thromboplastin Time (aPTT) </= 1.5x ULN
17) Adequate venous access
18) Karnofsky performance status >/= 70%
19) Afebrile at baseline/Day 0 prior to DNX-2401 administration (i.e., < 38.0 degrees Centigrade)
20) Prior anti-tumor therapies must have been completed within the following time periods prior to DNX-2401 injection: 4 weeks after nitrosoureas; 2 weeks after vincristine; 3 weeks after procarbazine or temozolomide; 4 weeks after bevacizumab, other antibody therapy or other anti-angiogenic therapy to treat glioblastoma; 5 half-lives for other anti-cancer agents including investigational agents (or 2 weeks after the last dose when the half-life is unknown). A discussion of these agents will take place with the Medical Monitor prior to establishing eligibility
21) External beam radiotherapy (> 5000 cGy) must have been completed at least 12 weeks prior to DNX-2401 administration
22) Females who are not of childbearing potential must be documented as such and will not be tested for pregnancy if they meet one or more of the following definitions of non-childbearing potential: >/= 45 years of age and has not had menses for greater than 2 years; amenorrheic for > 2 years without a hysterectomy and bilateral oophorectomy and a FSH value in the postmenopausal range upon pre-trial (screening) evaluation; post hysterectomy, bilateral oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
23) Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to receiving DNX-2401 injection. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible.
24) Female subjects of childbearing potential must be willing to use two highly effective birth control methods throughout the study, starting with the screening visit through 180 days after the single dose of DNX-2401 and 120 days after the last dose of pembrolizumab. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Examples of highly effective birth control methods include the following: Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm); birth control pills (The Pill); Depot or injectable birth control; Intrauterine Device (IUD); Birth control patch (e.g., Ortho Evra®); NuvaRing® (Note: Rhythm methods or abstinence alone is not considered to be an adequate method of contraception.)
25) Male subjects must agree to use an acceptable method of contraception throughout the study starting with DNX-2401 administration through 180 days after the single dose of DNX-2401 and 120 days after the last dose of pembrolizumab.
26) Willing and able to provide informed consent, undergo and comply with all study assessments and adhere to the protocol schedule
27) Agree not to donate blood or gametes following DNX-2401 administration
1) Recurrent GBM with multiple (> 2) separate enhancing tumors
(measurable or non-measurable)
2) Tumor shape that is bi-lobular or multifocal
3) Tumor involvement that would require ventricular, brainstem or posterior fossa injection or access through a ventricle or risk of ventricular penetration in order to deliver DNX-2401
4) Tumor involves both hemispheres or involves the subependyma or suspected cerebrospinal fluid (CSF) dissemination. Note: Extension of the tumor across the midline of the corpus callosum is consistent with contralateral hemisphere (bi-hemispheric) involvement, which is prohibited.
5) Documented extracranial metastases
6) 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 start of pembrolizumab (Note: An alternative management strategy may be considered following prior discussion with the DNAtrix Medical Monitor or designee. )
7) Uncontrolled blood-sugar levels defined as HbA1c > 7% on 2 separate measurements
8) Active autoimmune disease that requires or has required, systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9) Prior treatment with anti-PD1 or PD-L1 agents including pembrolizumab
10) Evidence of active, non-infectious pneumonitis
11) A history of interstitial lung disease
12) Transfusions or medications (e.g., G-CSF) to treat pancytopenia or other hematological conditions within 4 weeks prior to DNX-2401 administration
13) Prior gene transfer therapy or prior therapy with cytolytic virus of any type
14) Live vaccines of any kind within 45 days of DNX-2401 administration and while participating in the study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed
15) Major surgery within 4 weeks and minor surgery within 2 weeks of DNX-2401 administration. Note: If subject received major surgery, they must have fully recovered from the toxicity and/or complications from the intervention prior to receiving DNX-2401 or pembrolizumab.
16) Is currently participating and receiving investigational agent (s) or has participated in a study of an investigational agent(s) and received investigational agent(s) or used an investigational device within 30 days prior to DNX-2401 administration.
17) Any contraindication for undergoing MRI such as: individuals with pacemakers, epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel, metal prosthesis, implants with potential magnetic properties, metallic bodies in the eyes, etc.
18) Is pregnant or breastfeeding, or expecting to conceive or father children during the study, starting with the screening visit through 180 days after the single dose of DNX-2401 and 120 days after the last dose of pembrolizumab
19) Evidence of active uncontrolled infection or an unstable or severe intercurrent medical condition that requires treatment and/or precludes surgery
20) History of prior malignancy except for curatively treated basal or squamous cell carcinoma of the skin (non-melanoma skin cancer), cervical or vaginal intra-epithelial neoplasia, non-invasive breast cancer in situ or localized prostate cancer with a current prostate specific antigen (PSA) of < 4.0 ng/mL (mcg/L). Subjects with other curatively treated malignancies who had no evidence of metastatic disease and a > 2 year disease-free interval may be enrolled after approval by the DNAtrix Medical Monitor or designee.
21) Any medical condition that precludes intratumoral injection into the brain.
22) Immunocompromised subjects or those with autoimmune conditions, active hepatitis (HAV, HBV, HCV), known history of active TB (Mycobacterium tuberculosis), or human immunodeficiency virus (HIV) seropositivity. (Notes: TB testing is required for subjects recently exposed to persons with active tuberculosis or who have traveled recently to areas where TB is endemic. Active hepatitis B is defined as anti-HBc core antibody and HBsAg surface antigen positivity.)
23) Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery. If the medication can be discontinued > 1 week prior to DNX-2401 injection, then the subject may be eligible following consultation with the Medical Monitor. Low weight heparin and drugs in the anticoagulant class [e.g., Lovenox (enoxaparin)] administered on a temporary, limited basis for post-procedure DVT prophylaxis are permitted.
24) Encephalitis, multiple sclerosis or other central nervous system (CNS) infection or primary CNS disease that would interfere with subject evaluation
25) Li-Fraumeni Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways
26) Significant systemic or major illnesses including but not limited to: congestive heart failure, ischemic heart disease, kidney disease or renal failure, or organ transplantation
27) Alcohol or substance abuse or alcohol dependency that is active, within 12 months prior to screening that has caused health consequences (Refer to Appendix 3 for definitions)
28) History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the subject’s ability to participate in the study or the inability to obtain informed consent because of psychiatric or complicating medical problems
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
Frederick F. Lang
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