Pharmacological Class:
Proteasome inhibitor.

Active Ingredient(s):
Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

 Kyprolis的新药试验评估了266名复发性或者难治性多发性骨髓瘤的患者，这些患者至少预先接受两项治疗，包括(万珂)硼替佐米和萨立多胺治疗。Kyprolis以前主要用于大肠癌和胃肠道间质瘤。

FDA认为那些先前至少接受两种治疗包括蛋白酶抑制剂或者免疫调节剂(IMiD)的复发性或者难治性多发骨髓瘤患者使用Kyprolis（carfilzomib拟议的品牌名称）的效益风险评估是有益的。Onyx公司正在推动Kyprolis在多发性骨髓瘤中多线治疗中的应用。

Kyprolis的新药申请是在003-A1研究的基础上和其他更多研究数据的支持下进行的。003-A1研究是一个开放标签、单组2b阶段试验。这个试验评估了266名复发性或者难治性多发性骨髓瘤的患者，这些患者至少预先接受两项治疗，包括(万珂)硼替佐米和萨立多胺治疗。

Indication(s):
Treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Pharmacology:
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells.

Clinical Trials:
The safety and efficacy of Kyprolis were eva luated in a single-arm, multicenter clinical trial. Two hundred and sixty-six patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) were enrolled. Patients were enrolled in the trial whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial with total bilirubin levels ≥2 × upper limit of normal; CrCl <30mL/min; NYHA Class III to IV CHF; symptomatic cardiac ischemia; myocardial infarction (MI) within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion.

Kyprolis was administered intravenously over 2–10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20mg/m2 at each dose in Cycle 1, and 27mg/m2 in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia, and arthralgia, dexamethasone 4mg by mouth or by IV infusion was administered prior to all Kyprolis doses during the first cycle and prior to all Kyprolis doses during the first dose-escalation (27mg/m2) cycle. Dexamethasone premedication (4mg orally or intravenously) was reinstated if these symptoms reappeared during subsequent cycles.

The median number of cycles started was four.

The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N=266). The median duration of response was 7.8 months (95% CI: 5.6, 9.2).

Legal Classification:
Rx

Adults:
See literature. Premedicate with dexamethasone prior to all Cycle 1 doses, during 1st dose escalation and if infusion reactions occur. Give by IV over 2–10 minutes, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose, if tolerated increase to 27mg/m2 starting in Cycle 2 and subsequent cycles; continue until disease progression or unacceptable toxicity occurs. On dialysis: give dose after session. Toxicity dose modification: see literature.

Children:
Not established.

Warnings/Precautions:
Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs. Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reeva luate. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor platelets frequently during therapy. Hepatic impairment (monitor enzymes). Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

Adverse Reaction(s):
Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia; cardiac events, pulmonary HTN, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure.

How Supplied:
Single use vial—1

Last Updated:
7/30/2012