41-32 FDA Approves Varubi for Chemotherapy-Induced Nausea and Vomiting

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FDA Approves Varubi for Chemotherapy-Induced Nausea and Vomiting

FDA approved Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting.

Varubi, marketed by Tesaro Inc., is approved in adults in combination with other antiemetic agents that prevent nausea and vomiting associated with initial and repeat courses of vomit-inducing cancer chemotherapy.

Nausea and vomiting that occurs from 24 hours to up to 120 hours after the start of chemotherapy is referred to as delayed phase nausea and vomiting. Prolonged nausea and vomiting can lead to weight loss, dehydration and malnutrition in cancer patients leading to hospitalization.

Varubi is a substance P/neurokinin-1 receptor antagonist. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase. Varubi is provided to patients in tablet form.

The safety and efficacy of Varubi were established in three randomized, double-blind, controlled clinical trials where Varubi in combination with granisetron and dexamethasone was compared with a control therapy (placebo, granisetron and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic (such as cisplatin and the combination of anthracycline and cyclophosphamide) and moderately emetogenic chemotherapy drugs. Those patients treated with Varubi had a greater reduction in vomiting and use of rescue medication for nausea and vomiting during the delayed phase compared to those receiving the control therapy.

Varubi inhibits the CYP2D6 enzyme, which is responsible for metabolizing certain drugs. Varubi is contraindicated with the use of thioridazine, a drug metabolized by the CYP2D6 enzyme, because use of the two drugs together may increase the amount of thioridazine in the blood and cause an abnormal heart rhythm. The most common side effects in patients treated with Varubi include a low white blood cell count (neutropenia), hiccups, decreased appetite and dizziness.

The European Commission granted a marketing authorization for Unituxin (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation.

Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin.

The European approval was based on demonstration of improved event-free survival and overall survival in a multicenter, open-label, randomized trial (ANBL0032) sponsored by NCI under a Cooperative Research and Development Agreement with the drug’s sponsor, United Therapeutics Corp., and conducted by the Children’s Oncology Group.

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid arm or to RA alone. Patients in each arm received six cycles of treatment.

The Unituxin/RA arm consisted of Unituxin in combination with GM-CSF and RA (cycles 1, 3, and 5), Unituxin in combination with IL-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age, with a median age 3.8 years.

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death.

The primary intent-to-treat analysis found an improvement in EFS associated with Unituxin immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66 percent among subjects receiving Unituxin immunotherapy plus isotretinoin as compared with 48 percent in subjects receiving isotretinoin alone (log-rank test p = 0.033), although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses.

In addition, OS was evaluated with three years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive Unituxin immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80 percent compared with 67 percent among subjects receiving Unituxin immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165).

Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received Unituxin immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74 percent for Unituxin immunotherapy compared to 57 percent for isotretinoin alone (log-rank test p = 0.030).

The most frequently occurring adverse reactions reported during the neuroblastoma studies were hypotension, pain, hypersensitivity, pyrexia, urticaria, capillary leak syndrome, anemia, hypokalemia, decreased platelet count, hyponatremia, increased alanine aminotransferase, decreased lymphocyte count and decreased neutrophil count. Additional adverse reactions characteristic of an allergic response were also reported, including anaphylactic reaction and bronchospasm.

Unituxin is a monoclonal chimeric antibody composed of murine variable heavy and light chain regions and the human constant region for the heavy chain kappa, and reacts specifically with the ganglioside GD2, which is highly expressed on the surface of the neuroblastoma cells and minimally expressed on the surface of normal human neurons, peripheral pain fibres, and skin melanocytes.

In March, Unituxin, in combination with GM-CSF, IL-2 and RA, became the first therapy to be approved by FDA for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multi-agent multimodality therapy.

Unituxin carries a Boxed Warning alerting patients and health care professionals that Unituxin irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Unituxin may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression.

FDA granted Orphan Drug Designation to Toca 511 & Toca FC, an investigational immunotherapy treatment for glioblastoma developed by Tocagen.

The agency recently granted the drug Fast Track designation for the treatment of recurrent high-grade glioma, which includes glioblastoma and anaplastic astrocytoma. According to Tocagen, the drug is planned to move into a clinical trial later this year.

Toca 511 & Toca FC is an investigational treatment that is designed to program cancer cells to convert the prodrug 5-FC into the anticancer drug 5-FU, killing tumor cells and leading to activation of the immune system via a combination of mechanisms.

Toca 511 is a retroviral replicating vector that selectively delivers a gene for the enzyme cytosine deaminase to the tumor. Patients then take oral cycles of Toca FC, a novel formulation of an antifungal drug, which is converted within infected cancer cells into the FDA-approved anticancer drug, 5-fluorouracil. Immune activation locally in the tumor occurs through a combination of mechanisms that together break the barrier of immune tolerance and may lead to durable tumor response, according to Tocagen.

FDA granted Orphan Drug Designation for MTG-201, a therapy targeting Dickkopf-3 gene defects in various cancers, for the treatment of malignant mesothelioma.

The Dickkopf-3 gene produces a protein called REIC (Reduced Expression in Immortalized Cells protein), which is a critical protein in the downstream mechanism of apoptosis and when absent cancer cells cannot die.

By expressing REIC protein from within cancer cells, MTG-201 induces selective apoptosis due to ER stress, directly killing the cancer and reducing cancer burden. MTG-201 also stimulates the production of activated T-cell lymphocytes that specifically target and destroy residual cancer cells.

MTG-201, developed by MTG Biotherapeutics, is currently in phase I clinical trials for the treatment of prostate cancer and mesothelioma. Preclinical programs are ongoing for the treatment of liver and bladder cancers. MTG-201 is also being evaluated for efficacy in combination with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies.

FDA granted priority review for MCNA, developed by Telesta Therapeutics Inc.

The FDA completed its initial review of Telesta’s biologics license application and accepted it for filing. The agency set Feb. 27, 2016 as the review goal date for MCNA. The FDA has also advised that it will be organizing an advisory committee to discuss the BLA application.

MCNA is a biologic therapy developed to treat high-risk, non-muscle invasive bladder cancer patients who are refractory to or relapsing from front-line therapy, and is derived from the cell wall fractionation of a non-pathogenic bacteria. Its activity is believed to be through a dual mechanism of immune stimulation and direct anti-cancer effects.

MCNA was developed to be delivered as a sterile suspension for intravesical administration by urologists and urology nurses, following the same dosing paradigm as first-line bacillus Calmette-Guérin therapy. The efficacy, duration of responses and safety data from MCNA’s phase III trial was recently published in The Journal of Urology.


President Joe Biden’s proposed Advanced Research Projects Agency-Health would be a welcome partner to NCI—particularly in conducting large, collaborative clinical investigations, NCI Director Ned Sharpless said.“I think having ARPA-H as part of the NIH is good for the NCI,” Sharpless said April 11 in his remarks at the annual meeting of the American Association for Cancer Research. “How this would fit with the ongoing efforts in cancer at the NCI is still something to work out.”