FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation.

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 (95% CI, 5.6-12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.

Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary.

PURPOSE: On September 24, 2009, the U.S. Food and Drug Administration granted accelerated approval for Folotyn (pralatrexate injection, Allos Therapeutics, Inc.) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL); it is the first drug approved for this indication. EXPERIMENTAL DESIGN: This review was based on study PDX-008, a phase II, single-arm, nonrandomized, open-label, international, multicenter trial, designed to evaluate the safety and efficacy of pralatrexate when administered concurrently with vitamin B(12) and folic acid supplementation in patients with relapsed or refractory PTCL. RESULTS: The overall response rate was 27% in 109 evaluable patients [95% confidence interval (CI), 19-36%]. Twelve percent of 109 evaluable patients (95% CI, 7-20%)] had a response duration of ≥14 weeks. Six of these 13 patients achieved a complete response, and one patient had complete response unconfirmed. The most common grade 3 and 4 toxicities were thrombocytopenia, mucositis, and neutropenia. CONCLUSION: This accelerated approval was based on a response rate that is reasonably likely to predict clinical benefit in this heavily pretreated patient population with this rare disease. The applicant has committed to conducting postmarketing clinical trials to assess clinical benefit. The recommended starting dose of pralatrexate in patients with relapsed or refractory PTCL is 30 mg/m(2) via intravenous push over 3 to 5 min weekly for 6 weeks followed by a one-week rest (one cycle). Intramuscular injection of 1 mg vitamin B(12) should be administered every 8 to 10 weeks along with 1.0 mg folic acid given orally once a day.

Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

PURPOSE: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. EXPERIMENTAL DESIGN: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. RESULTS: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. CONCLUSIONS: On November 18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.

Fulvestrant in postmenopausal women with advanced breast cancer.

PURPOSE: Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA). EXPERIMENTAL DESIGN: The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized. RESULTS: Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes. CONCLUSIONS: FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.

Inflammation and hyperalgesia in rats neonatally treated with capsaicin: effects on two classes of nociceptive neurons in the superficial dorsal horn.

To address the mechanisms of hyperalgesia and dorsal horn plasticity following peripheral tissue inflammation, the effects of adjuvant-induced inflammation of the rat hindpaw on behavioral nociception and nociceptive neuronal activity in the superficial dorsal horn were examined in neonatally capsaicin-treated rats 6-8 weeks of age. Capsaicin treatment resulted in an 82% loss of unmyelinated fibers in L5 dorsal roots, a dramatic reduction of substance P-like immunoreactivity in the spinal cord, and a significant decrease in the percentage of dorsal horn nociceptive neurons that responded to C-fiber stimulation and noxious heating of the skin. The thermal nociceptive threshold was significantly increased in capsaicin-treated rats, but behavioral hyperalgesia to thermal stimuli still developed in response to inflammation. Following inflammation, there was a significant decrease in mechanical threshold and an increase in response duration to mechanical stimuli in both vehicle- and capsaicin-treated rats, suggesting that a state of mechanical hyperalgesia was also induced. The capsaicin treatment appears to have differential effects on nociceptive specific (NS) and wide-dynamic-range (WDR) neurons in inflamed rats. Expansion of the receptive fields of nociceptive neurons, a measure of the effect of inflammation-induced CNS plasticity, was less extensive for NS than for WDR neurons in capsaicin-treated rats. Compared to vehicle-treated rats, a smaller population of NS neurons, but a similar percentage of WDR neurons, had background activity in inflamed capsaicin-treated rats. C-fiber strength electrical stimulation of the sciatic nerve produced expansion of the receptive fields in a greater portion of NS neurons (53%, P < 0.05) in capsaicin- than in vehicle-treated rats (32%). There was no difference in stimulation-induced expansion of the receptive fields for WDR neurons between vehicle- or capsaicin-treated rats. An N-methyl-D-aspartate receptor antagonist, MK-801, attenuated the behavioral hyperalgesia and reduced the receptive field size of dorsal horn neurons in inflamed capsaicin- and vehicle-treated rats. The data suggest that while capsaicin-sensitive primary afferents may be involved in neuronal plasticity induced by peripheral tissue inflammation, changes in the capsaicin-insensitive WDR and NS populations are sufficient to produce thermal and mechanical hyperalgesia after the loss of capsaicin-sensitive primary afferents.

The misuse of analysis of variance to detect synergy in combination drug studies.

Drug combination studies often examine the possibility of synergy between drugs. Synergy is defined as an effect of a combination of drugs greater than that expected from the effects of the drugs given individually. One technique used by several investigators is the use of analysis of variance (ANOVA) to determine synergy. In this discussion, the argument is made that due to the pharmacology of drug combination studies the conditions necessary to support the use of ANOVA to detect synergy are typically not met. Therefore, the ANOVA technique is invalid for these drug combination studies.

Noradrenergic and opioid systems interact to alter the detection of noxious thermal stimuli and facial scratching in monkeys.

We examined the ability of the alpha 2-adrenoceptor agonist, ST-91, microinjected into the medullary dorsal horn (MDH), to diminish the sensory-discriminative features of noxious heat stimuli in awake behaving monkeys. Two monkeys performed a noxious thermal detection task and the time to detection of small increases in heat served as a measure of the perceived intensity of pain. ST-91 microinjected into the MDH (1.0, 3.0, 10.0 and 30.0 micrograms/0.4 microliter) produced dose-dependent increases in detection time to graded temperature increases (0.4-1.0 degrees C) from a noxious 46 degrees C base line. These dose-dependent effects were attenuated by the systemic administration of the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.), but not by the alpha 1-adrenoceptor antagonist, prazosin (0.5 mg/kg, i.m.) or the opioid-receptor antagonist, naloxone (0.5 mg/kg, i.m.). The effect of ST-91 on detection latency of thermal stimuli was not the result of alterations in attentional, motivational or motoric aspects of the monkeys' behavior, because detection of visual stimuli and non-noxious temperature coolings (36.0-34.5 degrees C) in a similar paradigm were not consistently altered. Microinjection of morphine (3.0 mg) into the MDH also increased detection latency of the noxious heat stimuli. Systemic administration of the opioid-receptor antagonist, naloxone (0.5 mg/kg), and the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.) attenuated these effects of morphine. In a separate experiment, morphine (5.0 micrograms) microinjected into the MDH induced facial scratching behavior. Idazoxan (2.0 mg/kg) was effective at attenuating this scratching behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a non-competitive NMDA receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation.

The involvement of NMDA receptors in rats with peripheral inflammation and hyperalgesia was evaluated by administration of the non-competitive NMDA receptor antagonist, MK-801. Inflammation and hyperalgesia was induced by intradermal injection of complete Freund's adjuvant (CFA) or carrageenan into the left hind paw. The latency of paw withdrawal from a thermal stimulus was used as a measure of hyperalgesia in awake rats. MK-801 (1.6 mg/kg, i.p., or 31.5 micrograms, intrathecal) significantly attenuated thermal hyperalgesia and reduced its duration in comparison to saline-injected rats (P less than 0.05). The receptive field size of nociceptive-specific and wide-dynamic-range neurons in the superficial and deep spinal dorsal horn recorded 24 h after injection of CFA was significantly reduced to 73 +/- 6% (P less than 0.05, n = 8) and 74 +/- 4% (P less than 0.05, n = 8) of control values, respectively, by a cumulative dose of 3 mg/kg of MK-801 (i.v.). MK-801 (2 mg/kg) prevented the expansion of the receptive fields of dorsal horn neurons recorded 5 +/- 0.4 h (n = 5) after intradermal injection of CFA as compared to saline-injected rats (P less than 0.05). MK-801 had no significant effect on receptive field size of dorsal horn neurons in rats without CFA-induced inflammation but blocked a transient expansion of the receptive fields induced by 1 Hz, C-fiber intensity electrical stimulation of the sciatic nerve. The background activity and noxious heat-evoked response of dorsal horn neurons in rats with CFA-induced inflammation were primarily inhibited and noxious pinch-evoked activity was both facilitated and inhibited by the administration of MK-801. These results support the hypothesis that NMDA receptors are involved in the dorsal horn neuronal plasticity and behavioral hyperalgesia that follows peripheral tissue inflammation.