Early Phase Study to Evaluate the MEK Inhibitor Selumetinib With the MDM2 Inhibitor APG-115 in Patients With Neurofibromatosis Type 1 and Pre-malignant and Malignant Peripheral Nerve Sheath Tumors
Overview
- Phase
- Phase 1
- Intervention
- APG-115
- Conditions
- Malignant Peripheral Nerve Sheath Tumor (MPNST)
- Sponsor
- AeRang Kim
- Enrollment
- 45
- Locations
- 1
- Primary Endpoint
- The number of treated patients with adverse events as determined by the common criteria for adverse version 5 (CTCAEv5).
- Status
- Not yet recruiting
- Last Updated
- 10 months ago
Overview
Brief Summary
This is a phase 0/1/2, multi-site study to evaluate the MEK inhibitor Selumetinib with the MDM2 Inhibitor APG-115 in patients with Neurofibromatosis Type 1 and pre-malignant and malignant peripheral nerve sheath tumors
Detailed Description
The first primary objective of the study is to determine the safety, tolerability, pharmacokinetics, and recommended doses of selumetinib and APG-115 in patients with Neurofibromatosis Type 1 (NF1) and refractory/unresectable MPNST (Part A). The second primary objective is to determine the clinical benefit of selumetinib and APG-115 in patients with NF1 and refractory/unresectable MPNST (Part B). The secondary objective is to evaluate the percent apoptosis and tumor proliferation in resectable atypical neurofibromatus neoplasm of uncertain biologic potential (ANNUBP) after exposure to selumetinib and APG-115 (Part C)
Investigators
AeRang Kim
Pediatric Oncologist
Children's National Research Institute
Eligibility Criteria
Inclusion Criteria
- •AGE: Part A and C: ≥ 18 years of age AGE: Part B: ≥12 years (minimum BSA ≥0.55m2)
- •Part A and B: Patients with unresectable or metastatic histologically confirmed NF1 associated MPNST. Part C: Patients with NF1 and ANNUBP. Diagnostic criteria based on Miettinen et al, Human Pathol:
- •MEASURABLE DISEASE: Patients must have measurable disease by RECISTv1.
- •Baseline radiologic scans must be performed within 4 weeks of starting treatment.
- •Therapeutic options: Parts A and B: Patients must have experienced progression after one or more prior regimens of cytotoxic chemotherapy. Patients who have refused cytotoxic chemotherapy or for whom treatment on this protocol prior to receiving cytotoxic chemotherapy is felt to be in the best interest for the patient by the local investigator will also be eligible. Part C: Patients with ANNUBP that are planned for surgical resection
- •PRIOR THERAPY
- •Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study excluding chronic grade 1 toxicities and alopecia.
- •No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry.
- •Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks (≥21 days) prior to study entry (42 days if prior nitrosourea).
- •Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry.
Exclusion Criteria
- •History of another primary malignancy except for:
- •A malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of the study intervention and of low potential risk of recurrence.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated carcinoma in situ without evidence of disease
- •Stable optic pathway glioma or low-grade glioma not receiving active therapy
- •History of leptomeningeal carcinomatosis
- •Patients receiving other anti-cancer agents are not eligible.
- •Patients who cannot swallow whole pills.
- •Current or prior use of immunosuppressive medications within 14 days prior to study entry. The following are exceptions to this criterion:
- •Intranasal, inhaled, topical steroids or local steroid injection (e.g., intra-articular injection)
Arms & Interventions
APG-115 and Selumetinib
There is only one arm. It is combination therapy of APG-115 and Selumetinib.
Intervention: APG-115
APG-115 and Selumetinib
There is only one arm. It is combination therapy of APG-115 and Selumetinib.
Intervention: Selumetinib
Outcomes
Primary Outcomes
The number of treated patients with adverse events as determined by the common criteria for adverse version 5 (CTCAEv5).
Time Frame: 15 months
We will be looking at safety and dose recommendations using adverse event evaluation per dose level as determined by CTCAEv5 (Part A)
Tumor response by imaging using RECISTv1.1
Time Frame: 28 months
We will determine the clinical benefit of this combination by evaluating tumor response by imaging using RECISTv1.1 guidelines (Part B)
Secondary Outcomes
- Percent apoptosis and tumor proliferation(12 months)