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FDA Approval of Companion Diagnostic for BRAF Inhibitor Therapeutics in Melanoma

The FDA approved FoundationOneCDx to be used as a companion diagnostic for two groups of current and future FDA-approved therapeutics in melanoma, which include BRAF inhibitor monotherapies targeting BRAFV600E and BRAF/MEK inhibitor combination therapies targeting BRAFV600E or V600K mutations. This approval makes FoundationOneCDx the only comprehensive genomic profiling test approved as a companion diagnostic across two groups of targeted therapies, representing an important step toward simplifying decision making for oncologists.

FDA; cancer research... - Click to enlarge in new windowFDA; cancer research; clinical trials. FDA; cancer research; clinical trials

This approval represents an innovative, more efficient regulatory approach that simplifies the companion diagnostic approval process for biopharma companies developing BRAF inhibitor therapeutics, while maintaining rigor and high-quality standards.


FoundationOne CDx is a next-generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability and tumor mutational burden using DNA isolated from formalin-fixed, paraffin-embedded tumor tissue specimens. FoundationOne CDx is for prescription use only and is intended as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with their approved therapeutic product labeling. Additionally, it is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy.


Clearance for Phase Ib/II Trial of Anti-CTLA-4 MAB ADG116 With Pembrolizumab

The FDA has cleared an Investigational New Drug (IND) application to proceed with a Phase Ib/II clinical trial of an anti-CTLA-4 monoclonal antibody (mAb), ADG116, in combination with the anti-PD-1 antibody, pembrolizumab. The global trial (ADG116-P001/KEYNOTE-C97) will evaluate patients with advanced/metastatic solid tumors at multiple sites in the U.S. and Asia Pacific.


ADG116 is designed to target a unique conserved epitope of CTLA-4 with enhanced efficacy by potent Treg depletion in the tumor microenvironment. ADG116 is designed with a soft ligand blocking to address safety concerns associated with existing CTLA-4 therapeutics.


The ADG116-P001 trial is expected to dose the first patient in early 2022, and is designed to evaluate the safety and tolerability, determine the maximum tolerated dose, and assess preliminary efficacy of the combination of ADG116 and pembrolizumab.


Additionally, the ongoing ADG116-1003 trial is on track to expand with two combination cohorts investigating safety and preliminary efficacy of ADG116 with either toripalimab or ADG106 in patients with advanced/metastatic solid tumors.


FDA Clearance of IND Application for microRNA Candidate INT-1B3

The FAD granted Investigational New Drug (IND) clearance for a Phase I clinical trial evaluating miRNA candidate, INT-1B3, in patients with advanced solid tumors. INT-1B3 is a lipid nanoparticle (LNP) formulated, chemically modified mimic of the endogenous tumor suppressor, miR-193a-3p, and represents a promising novel therapeutic approach that is designed to simultaneously address multiple hallmarks of cancer.


The IND approval enables researchers to expand the number of clinical sites and to facilitate the enrollment of patients for the dose expansion (Phase Ib) part of the trial in the U.S. The first part of the Phase I trial was initiated in Europe at the beginning of 2021, with the dosing of the first patient in the dose escalation (Phase Ia) part in February. The treatment of the first patient in the Phase Ib cohort is planned for the second half of 2022.


The multicentric, open-label, multiple ascending dose Phase I/Ib trial (NCT04675996) will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of INT-1B3 in patients with advanced solid tumors. The study is expected to enroll a total of up to 80 patients in the U.S. and Europe. The Phase Ia part of the trial is currently ongoing in the Netherlands and Belgium and will enroll approximately 30 patients with advanced solid tumors. In the second part (Phase Ib) of the trial, approximately 50 patients with hepatocellular carcinoma or triple-negative breast cancer will be enrolled in the U.S. and Europe. Topline results from the Phase Ia part of the study are expected in the first half of 2022.


INT-1B3's unique mechanism of action addresses multiple hallmarks of cancer simultaneously. It directly targets tumor cells and the tumor microenvironment by specific modulation of multiple signaling pathway components across the PTEN tumor suppressor pathway and the oncogenic PI3K/Akt and Ras/MAPK pathways resulting in inhibition of proliferation and migration and induction of cell cycle arrest and apoptosis. The triggering of the immunogenic tumor cell death process, as well as downregulation of the adenosine-A2A receptor pathway through inhibition of CD39/CD73, leads to a decrease in immunosuppressive FoxP3/Lag3 regulatory T cells and monocytic myeloid-derived suppressor cells, and maturation of dendritic cells. As a result, the immune system is activated, and long-term immunity is triggered by recruitment of CD8+ effector T cells leading to decreased metastasis development and improved animal survival compared to anti-PD1 treatment.


Daratumumab + Hyaluronidase-Fihj & Carfilzomib + Dexamethasone for Multiple Myeloma

The FDA approved daratumumab + hyaluronidase-fihj and carfilzomib plus dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy.


Efficacy was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. This cohort enrolled 66 patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy. Patients received 1,800 mg daratumumab and 30,000 units hyaluronidase administered subcutaneously in combination with carfilzomib (20/70 mg/m2 once weekly regimen) and dexamethasone.


The main efficacy outcome measure was overall response rate (ORR). The ORR was 84.8 percent (95% CI: 73.9%, 92.5%). At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2 percent (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5 percent (95% CI: 68.9, 90.6) maintained response for at least 9 months.


The most common adverse reactions (>=20%) occurring in patients treated with daratumumab + hyaluronidase-fihj, carfilzomib, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.


The recommended dose is 1,800 mg daratumumab and 30,000 units hyaluronidase administered subcutaneously once weekly from Weeks 1-8, once every 2 weeks from Weeks 9-24, and once every 4 weeks starting Week 25 until disease progression or unacceptable toxicity.


The recommended dosage regimens of carfilzomib when administered in combination with daratumumab and hyaluronidase-fihj are the following: 1) Once weekly 20/70 mg/m2 regimen: carfilzomib 20 mg/m2 administered by IV infusion over 30 minutes on Cycle 1 Day 1 and if a dose of 20 mg/m2 is tolerated, 70 mg/m2 as a 30-minute IV infusion on Cycle 1, Day 8 and Day 15, and then Day 1, 8, and 15 of each 28-day cycle. 2) Twice weekly 20/56 mg/m2 regimen: carfilzomib 20 mg/m2 administered by IV infusion over 30 minutes on Cycle 1 Day 1 and Day 2 and, if a dose of 20 mg/m2 is tolerated, 56 mg/m2 administered by IV infusion over 30 minutes on Cycle 1, Day 8, 9, 15, and 16, and then on Day 1, 2, 8, 9, 15, 16 of each 28-day cycle.