FDA Approval Summary: Asciminib for Ph+ CML in Chronic Phase Treated with Two or More Tyrosine Kinase Inhibitors and for the T315I Mutation.

On October 29, 2021, FDA granted accelerated approval to asciminib (Scemblix; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL Study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% (95% CI: 30, 46) in the asciminib arm vs. 16% (95% CI: 8, 26) in the bosutinib arm (p-value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI: 34, 64) in the single-arm CABL001X2101 Study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, increases in creatine kinase, ALT, AST, lipase, and amylase. This manuscript describes the basis for approval of these indications.

Perspectives on Drug Development for the Treatment of Chronic Myeloid Leukemia in Pregnant Patients and Patients Who Are Breastfeeding.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by U.S. Food and Drug Administration to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. As patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care.

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes.

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

FDA Approval Summary: Oral Azacitidine for Continued Treatment of Adults with Acute Myeloid Leukemia Unable to Complete Intensive Curative Therapy.

On September 1, 2020, the FDA granted approval for oral azacitidine (Onureg, CC-486) for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and who are not able to complete intensive curative therapy. Approval was based on improvement in overall survival using CC-486 300 mg daily in a 2 weeks on/2 weeks off schedule in comparison with placebo (HR, 0.69; 95% confidence interval, 0.55-0.86; P = 0.0009) in the randomized trial CC-486-AML-001 (QUAZAR) in adults ≥ 55 years old with AML in CR/CRi who did not complete standard intensive induction and postremission therapy. Of note, the study was not designed to test CC-486 as maintenance after standard postremission therapy or as an alternative to standard postremission therapy. Gastrointestinal toxicities, fatigue, and pneumonia were more common in patients treated with CC-486 compared with placebo. Additional studies are needed to establish safe dosing for patients with hepatic impairment. The pharmacokinetic parameters, recommended dose, and recommended schedule of CC-486 differ substantially from those of other azacitidine formulations; therefore, inappropriate substitutions between formulations pose a considerable risk for harm.

FDA Approval: Blinatumomab.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit.

Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum.

RATIONALE: Acute systemic administration of salvinorin A, a naturally occurring kappa-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow. OBJECTIVES: Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed. MATERIALS AND METHODS: Salvinorin A was administered via the dialysis probe (0; 20-200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day x 5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment. RESULTS: Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced. CONCLUSIONS: These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ.

Repeated Cocaine Experience Facilitates Sucrose-Reinforced Operant Responding in Enriched and Isolated Rats.

The purpose of the present experiment was to determine whether repeated cocaine exposure differentially affects sucrose-reinforced operant responding in rats raised in an enriched condition (EC) or an isolated condition (IC). Specifically, the performance of EC and IC rats pressing a lever for sucrose under a high fixed-ratio schedule (FR 30) prior to and after 10 days of exposure to cocaine (15 mg/kg, i.p.) or saline was compared. Regardless of rearing condition, rats repeatedly exposed to cocaine had shorter reacquisition latencies to complete a sucrose-reinforced FR 30 task than saline controls. The results suggest that cocaine exposure may have cross-sensitized both EC and IC rats to the reinforcing effects of sucrose or sucrose-associated cues, thus facilitating reacquisition of operant responding.

Monoamine-depleting doses of methamphetamine in enriched and isolated rats: consequences for subsequent methamphetamine-induced hyperactivity and reward.

The current study examined whether environmental enrichment alters the effects of monoamine-depleting doses of methamphetamine on subsequent methamphetamine-induced hyperactivity and conditioned place preference. Rats were raised in either an enriched or isolated condition from 21 to 55 days of age and then were treated with monoamine-depleting doses of methamphetamine (10 mg/kg, four injections at 2 h intervals) or saline. Eight days later, rats were assessed for methamphetamine-induced (0.3 or 1.0 mg/kg) hyperactivity and conditioned place preference. Results indicated that the monoamine-depleting dose regimen produced a similar hyperthermic response in enriched and isolated rats. Enriched and isolated rats also displayed a similar depletion of dopamine in the striatum and serotonin in nucleus accumbens. The monoamine-depleting dose regimen, however, enhanced methamphetamine hyperactivity across repeated conditioning sessions in enriched rats, but not in isolated rats. In contrast to isolated rats, enriched rats failed to display significant conditioned place preference to the low dose of methamphetamine (0.3 mg/kg) following the monoamine-depleting dose regimen, suggesting that the rewarding effect of methamphetamine was blunted by the combined effect of enrichment and methamphetamine treatment. Thus, environmental enrichment may exacerbate the behavioral consequences of monoamine-depleting doses of methamphetamine.

Lobeline does not serve as a reinforcer in rats.

RATIONALE: Previous results demonstrated that pretreatment with lobeline attenuates d-methamphetamine self-administration in rats. OBJECTIVE: The present experiments determined if lobeline serves as a reinforcer, if it decreases d-methamphetamine-induced reinstatement of d-methamphetamine self-administration, and if it activates the mesolimbic and nigrostriatal dopamine (DA) pathways in Sprague-Dawley male rats. METHODS: The ability of intravenous (IV) lobeline (0.015-0.15 mg/kg per infusion) to engender responding and the ability of lobeline (0.015 and 0.05 mg/kg per infusion) to substitute for d-methamphetamine was determined using the self-administration paradigm. Experiments were also performed to determine if lobeline (1.0 and 3.0 mg/kg) reinstates responding for d-methamphetamine or alters the ability of d-methamphetamine (1.0 mg/kg per infusion) to reinstate responding following extinction. The effect of lobeline (3.0 mg/kg) or d-methamphetamine (1.0 and 3.0 mg/kg) on DA and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and striatum were also determined. RESULTS: Lobeline was not self-administered and did not substitute for d-methamphetamine. Also, lobeline did not reinstate responding for d-methamphetamine following extinction nor did it alter d-methamphetamine-induced reinstatement. Furthermore, lobeline did not alter DA or DOPAC levels in the either the nucleus accumbens or striatum. CONCLUSIONS: Taken together, the present results indicate that lobeline decreases d-methamphetamine self-administration by decreasing reward, not by acting as a substitute reinforcer.

Effects of opioid antagonists on unconditioned and conditioned hyperactivity to morphine.

In a series of experiments, the ability of selective mu- (beta-funaltrexamine, beta-FNA), delta- (naltrindole, nalt) and kappa- (nor-binaltorphimine, nor-BNI) opioid receptor antagonists to attenuate the unconditioned and conditioned hyperactive effects of morphine was examined. For comparison, the nonselective opioid receptor antagonist naloxone (nalx) was also examined. Locomotor activity served as the behavioral measure. Experiment 1 found that doses of 1 and 4, but not 16 mg/kg, of morphine effectively produced conditioned hyperactivity (CH). Experiments 2a-d found that beta-FNA, nalt, nor-BNI and nalx, respectively, attenuated unconditioned morphine-induced hyperactivity. Experiments 3a-c, however, found that none of the selective antagonists, given individually, attenuated CH. In contrast, nalx did attenuate CH (Experiment 3d). Collectively results suggest that the unconditioned and conditioned hyperactive responses to morphine are mediated by different receptor systems and that activation of multiple opioid-receptor subtypes mediate expression of CH.