Melanoma
Conditions
Brief summary
The goal of this clinical research study is to find the recommended dose level and recommended number of injections of the study agent DNX-2401 that can be given to patients with metastatic melanoma that have intracranial and/or extracranial lesions.
Detailed description
Primary Objectives: Group A: • To determine the safety and tolerability of DNX-2401, a conditionally replication-competent adenovirus (AdV), administered to intracranial lesions in patients with metastatic melanoma as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. (Appendix 2) with evidence of stable extracranial disease, according to RECIST v1.1 criteria, while on immunotherapy. Group B: • To determine the safety and tolerability of DNX-2401, a conditionally replication-competent adenovirus (AdV), administered to extracranial lesions in patients with metastatic melanoma as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. (Appendix 2) with evidence of extracranial disease progression, according to RECIST v1.1 criteria, while on immunotherapy." Secondary Objectives: (All Cohorts) * To evaluate the overall safety profile of DNX-2401 injected into melanoma metastases. * To evaluate antitumor activity of DNX-2401. Exploratory Objective (Window of Opportunity Cohort) • Correlative analysis of intracranial and extracranial tissue to understand immunologic features associated with response and resistance to treatment with DNX-2401. Exploratory Objectives (All Cohorts) * To evaluate the utilization of steroids for symptomatic intracranial metastases during the course of DNX-2401 treatment * To evaluate functional outcomes following DNX-2401 treatment * To differentiate between systemic and intracranial treatment response * To evaluate for imaging evidence of immune mediated treatment response
Interventions
DRUGDNX-2401
Given by injection
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(For both Groups): Patients must be 18 years old and above with stage IV melanoma. Patients must have ECOG Performance status of 0 or 1 (may be obtained from medical records within 24 days of screening if not performed at screening). Patients must have an expected life expectancy of ≥3 months based on physician assessment. Patients must be able to complete an MRI of the head with contrast. For women of childbearing potential only, a negative urine or serum pregnancy test is required at screening. (Note: The test may need to be repeated within 7 days of oncolytic viral administration if the investigational procedure is delayed). Women must be willing to notify investigator immediately if they become pregnant at any time during the trial period. Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 6 months from administration of virus. Birth control that is acceptable to use in this study: 1. 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) 2. Birth control pills ("The Pill") 3. Depot or injectable birth control 4. IUD (Intrauterine Device) 5. Birth Control Patch (e.g., Othro Evra®) 6. NuvaRing® 7. Surgical sterilization (i.e., tubal ligation or hysterectomy for women or vasectomy for men) Patients must be able and willing to provide written informed consent prior to performance of any study-related procedure. A legally authorized representative (LAR) may provide consent if the potential subject lacks the capacity to provide consent themselves. Patient assent will be sought where feasible in this situation. For patients enrolled in Groups A and B, patients must continue with immunotherapy while undergoing oncolytic viral treatment at the discretion of the medical oncologist. Normal hematologic, renal and liver function as defined by: ANC ≥1000/ mm3 AGC ≥1500/ mm3 WBC ≥3000/mm3 Platelets ≥100,000/ mm3 PT, INR or PTT \<1.5 x institutional upper limit Hemoglobin \>8.0 g/dL Total serum bilirubin ≤ 1.5 upper normal institutional limits AST(SGOT)/ALT(SGPT) ≤2 × institutional upper limit of normal; ≤5 ULN if there is liver involvement secondary to the tumor Serum creatinine ≤ 1.5 x ULN OR ≥40 mL/min for participant with creatinine levels \> 1.5 x institutional ULN This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race or cognitive status. Minorities will actively be recruited to participate. (For Group A): Patients must have radiographic evidence of stable extracranial disease or no evidence of extracranial disease on current immunotherapy regimen based on RECIST v1.1 criteria. Patients must have between one and five brain metastases, identified on the screening MRI, from histologically confirmed metastatic melanoma. At least one of those lesions must be untreated, be suitable for accurate repeated measurements and have a tumor diameter of either 0.5-3.5cm (GroupA-Arm1) or 0.5-2.0cm (GroupA-Arm2) on the screening magnetic resonance imaging \[MRI\]) in at least one dimension. One of those lesions will be designated as the index lesion and planned for stereotactic intraoperative biopsy and oncolytic viral administration. The other four may be newly diagnosed, stable or recurrent. All intracranial metastases (the index lesion, and the non-index lesions, as defined below) must be located \>5 mm from the optic chiasm and outside the brainstem. The brain metastases must be an independently verified measurable brain metastasis in accordance with the mRECIST (Appendix 1) by Neuro Radiology. * Previous radiation and/or excision of brain metastases are permitted, provided that neurologic sequelae have completely resolved and at least one untreated lesion(s) remain. o Patients treated with SRS or surgical resection but who have one or more measurable lesion(s) that remained untreated will be eligible and the untreated lesions will be considered measurable target lesions. * Patients in Group A will need to consent to have a biopsy of the intracranial index lesion taken at the time of the stereotactic oncolytic viral injection, before each injection of oncolytic virus. This is to obtain histologic confirmation of the tumor. * For patients enrolled in Group A-Arm1, the index lesion must be surgically accessible for both stereotactic viral inoculation and surgical resection at the discretion of the treating neurosurgeon at the time of patient enrollment. For patients enrolled into GroupA-Arm2, the index lesion must be surgically accessible for stereotactic viral inoculation at the discretion of the treating neurosurgeon. Amongst patients in DL2 or DL3 of Arm A.2, if the pre-treatment biopsy at the second or third viral inoculation does not demonstrate viable tumor, the patient will be moved to the prior Dose Level (e.g. patient in DL2 moved to DL1 or patient in DL3 moved to DL1 or 2 depending on how many viral injections the patient received). Index lesions in GroupA-Arm1 and GroupA-Arm2 that are located in or near eloquent cortex, as defined as the sensorimotor strip, speech and memory cortices, or proximity to corticospinal tracts, must be reviewed and approved by the enrolling neurosurgeon. Non-index lesions, which are not planned for oncolytic virus administration, must measure up to 4.0 cm in maximal extent on the screening MRI brain scan. The non-index lesion(s) can be treated with SRT or surgical resection at the discretion of the radiation oncologist and neurosurgeon. (For Group B): Patients must have radiographic evidence of progressive extracranial disease on current immunotherapy regimen based on RECIST v1.1 criteria. Patients enrolled in Group B must have at least 1 injectable extracranial lesion amenable for direct injection or through the use of image guidance, such as ultrasound. The lesion must be an injectable cutaneous, subcutaneous, or nodal melanoma lesion greater than or equal to 5mm in at least one dimension. Patients enrolled in Group B can have up to 5 intracranial metastases up to 4.0 cm in size; however, the presence of intracranial metastases is not a requirement for patients enrolled in this Arm. For patients with intracranial metastases, these lesions can be treated with SRT, surgical resection, or WBRT at the discretion of the radiation oncologist and neurosurgeon.
Exclusion criteria
(For Both Groups): Patients with \>5 diagnosed intracranial metastases on screening MRI Patients who received prior WBRT or SRT for brain metastases within 2 days of study treatment initiation Patients who received high dose corticosteroids defined as dexamethasone greater than 2mg per day within 7 days of initiating therapy. However, if they have been on a stable dose of 2 mg or less per day for 7 days they can be enrolled. Patients with suspected or confirmed leptomeningeal disease defined as radiographic evidence by MRI of leptomeningeal involvement in addition to positive cerebrospinal fluid (CSF) cytology Serum lactate dehydrogenase ≥1.5x upper limit of normal Primary uveal or mucosal melanoma Active uncontrolled infection or unstable or severe intercurrent medical conditions which would impact the ability to participate in the study. All patients must be afebrile at baseline and not taking antiviral or oral antibiotics. 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, based on the clinical judgment of the surgeon, prior to oncolytic viral administration, the patient may be eligible. Past radiation or surgical therapy to the index lesion is exclusionary. However, up to a total of 2 prior courses of radiation treatment or surgical resection to non-index lesions are allowed as long as any treated lesions were \>15mm from the index lesion. Known infections with hepatitis B (positive HBsAg), hepatitis C (positive hepatitis C RNA), or HIV Patients with known or suspected immunosuppressive disorders, such as acquired or congenital/ immune deficiency syndromes and autoimmune diseases Tumor position that, in the Investigator's opinion, would require ventricular, brainstem or posterior fossa injection in order to deliver the virus 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. Inoculation with a live vaccine within 30 days prior to oncolytic virus administration History of encephalitis, multiple sclerosis, other CNS infection or primary CNS disease that would interfere with subject evaluation Females who are pregnant or lactating females who are breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Adverse Events (AEs) | Through study completion; an average of 1 year | Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 |
Countries
United States
Contacts
CONTACTChristopher Alvarez-Breckenridge, MD, PHD
PRINCIPAL_INVESTIGATORChristopher Alvarez-Breckenridge, MD, PHD
M.D. Anderson Cancer Center
Outcome results
None listed