February 6, 2016
Recommended Topic Related To:

Cyramza

"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.

Akman pleaded guilty in the U.S. District Court"...

A A A

Cyramza

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligandstimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.

Pharmacokinetics

The pharmacokinetic (PK) characteristics of ramucirumab are similar for patients with gastric cancer, NSCLC, and mCRC based on a population PK analysis. The mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 L/hour (30%) and the mean terminal half-life was 14 days (20%).

Specific Populations

Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis.

Renal Impairment: Based on a population PK analysis, no clinically meaningful differences in the average concentration of ramucirumab at steady state (Css) were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n=687), moderate (CLcr 30-59 mL/min, n=244) or severe (CLcr 15-29 mL/min, n=6) renal impairment compared to patients with normal renal function (CLcr ≥ 90 mL/min, n=697).

Hepatic Impairment: Based on a population PK analysis, no clinically meaningful differences in the average Css of ramucirumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] and AST > ULN, or total bilirubin > 1.0-1.5 times ULN and any AST, n=525), or moderate (total bilirubin > 1.5-3.0 times ULN n=23) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN, n=1055). No PK data are available from patients with severe hepatic dysfunction (total bilirubin > 3.0 times ULN and any AST).

Drug Interaction Studies

No clinically meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the approved combinations, including paclitaxel, docetaxel, and irinotecan (or its active metabolite, SN-38), were observed in patients with solid tumors.

Animal Toxicology And/Or Pharmacology

Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent).

A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.

Clinical Studies

Gastric Cancer

Study 1 was a multinational, randomized, double-blind, multicenter study of CYRAMZA plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum-or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients received either an intravenous infusion of CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months ( ≥ 10% versus < 10%), geographic region, and location of the primary tumor (gastric versus GEJ).

Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were W hite, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.

Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA as compared to patients randomized to receive placebo. Efficacy results are shown in Table 6 and Figure 1.

Table 6: Randomized Trial of CYRAMZA plus BSC versus Placebo plus BSC in Gastric Cancer

  CYRAMZA
N=238
Placebo
N=117
Overall Survival
  Number of deaths (%) 179 (75%) 99 (85%)
  Median - months (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)
  Hazard Ratio (95% CI) 0.78 (0.60, 0.998)
  Stratified Log-rank p-value 0.047
Progression-free Survival
  Number of events (%) 199 (84%) 108 (92%)
  Median - months (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4)
  Hazard Ratio (95% CI) 0.48 (0.38, 0.62)
  Stratified Log-rank p-value < 0.001
Abbreviations: CI = confidence interval

Figure 1: Kaplan-Meier Curves of Overall Survival -CYRAMZA plus BSC versus Placebo plus BSC in Gastric Cancer

Kaplan-Meier Curves of Overall Survival - Illustration

Study 2 was a multinational, randomized, double-blind study of CYRAMZA plus paclitaxel versus placebo plus paclitaxel that randomized (1:1) 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum-and fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. Randomization was stratified by geographic region, time to progression from the start of first-line therapy ( < 6 months versus ≥ 6 months) and disease measurability.

Patients were randomized to receive either CYRAMZA 8 mg/kg (n=330) or placebo (n=335) as an intravenous infusion every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m² by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced in increments of 10 mg/m² for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate.

Demographics and baseline characteristics were similar between treatment arms including the following: Median age was 61 years; 71% of patients were men; 61% were W hite, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 78% of patients had measurable disease; 79% of patients had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy.

Overall survival, progression-free survival, and objective response rate were statistically significantly improved in patients randomized to receive CYRAMZA plus paclitaxel compared to patients randomized to receive placebo plus paclitaxel. Efficacy results are shown in Table 7 and Figure 2.

Table 7: Randomized Trial of CYRAMZA plus Paclitaxel versus Placebo plus Paclitaxel in Gastric Cancer

  CYRAMZA + paclitaxel
N=330
Placebo + paclitaxel
N=335
Overall Survival
  Number of deaths (%) 256 (78%) 260 (78%)
  Median - months (95% CI) 9.6 (8.5, 10.8) 7.4 (6.3, 8.4)
  Hazard Ratio (95% CI) 0.81 (0.68, 0.96)
  Stratified Log-rank p-value 0.017
Progression-free Survival
  Number of events (%) 279 (85%) 296 (88%)
  Median - months (95% CI) 4.4 (4.2, 5.3) 2.9 (2.8, 3.0)
  Hazard Ratio (95% CI) 0.64 (0.54, 0.75)
  Stratified Log-rank p-value < 0.001
Objective Response Rate (CR + PR)
  Rate - percent (95% CI) 28 (23, 33) 16 (13, 20)
  Stratified CMH p-value < 0.001
Abbreviations: CI = confidence interval, CR = complete response, PR = partial response, CMH = Cochran-Mantel-Haenszel

Figure 2: Kaplan-Meier Curves of Overall Survival -CYRAMZA plus Paclitaxel versus Placebo plus Paclitaxel in Gastric Cancer

Kaplan-Meier Curves of Overall Survival - Illustration

Non-Small Cell Lung Cancer

Study 3 was a multinational, randomized, double-blind, study of CYRAMZA plus docetaxel versus placebo plus docetaxel, that randomized (1:1) 1253 patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. Patients were also required to have ECOG PS 0 or 1. Patients were randomized to receive either CYRAMZA at 10 mg/kg or placebo by intravenous infusion, in combination with docetaxel at 75 mg/m² every 21 days. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m² every 21 days. Patients who discontinued combination therapy because of an adverse event attributed to either CYRAMZA/placebo or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity. Randomization was stratified by geographic region, gender, prior maintenance therapy, and ECOG PS.

Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 82% were W hite and 13% were Asian; 32% had ECOG PS 0; 73% had nonsquamous histology and 26% had squamous histology. In addition to platinum chemotherapy (99%), the most common prior therapies were pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%). Twenty-two percent of patients received prior maintenance therapy. Tumor EGFR status was unknown for the majority of patients (65%). W here tumor EGFR status was known (n=445), 7.5% were positive for EGFR mutation (n=33). No data were collected regarding tumor ALK rearrangement status.

Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA plus docetaxel compared to patients randomized to receive placebo plus docetaxel. Objective response rate (complete response + partial response) was 23% (95% CI: 20, 26) for CYRAMZA plus docetaxel and 14% (95% CI: 11, 17) for placebo plus docetaxel, p-value of < 0.001. Efficacy results are shown in Table 8 and Figure 3.

Table 8: Randomized Trial of CYRAMZA plus Docetaxel versus Placebo plus Docetaxel in NSCLC

  CYRAMZA + docetaxel
N=628
Placebo + docetaxel
N=625
Overall Survival
  Number of deaths (%) 428 (68%) 456 (73%)
  Median - months (95% CI) 10.5 (9.5, 11.2) 9.1 (8.4, 10.0)
  Hazard Ratio (95% CI) 0.86 (0.75, 0.98)
  Stratified Log-rank p-value 0.024
Progression-free Survival
  Number of events (%) 558 (89%) 583 (93%)
  Median - months (95% CI) 4.5 (4.2, 5.4) 3.0 (2.8, 3.9)
  Hazard Ratio (95% CI) 0.76 (0.68, 0.86)
  Stratified Log-rank p-value < 0.001
Abbreviations: CI = confidence interval

Figure 3: Kaplan-Meier Curves of Overall Survival - CYRAMZA plus Docetaxel versus Placebo plus Docetaxel in NSCLC

Kaplan-Meier Curves of Overall Survival - Illustration

Colorectal Cancer

Study 4 was a multinational, randomized, double-blind, study of CYRAMZA plus FOLFIRI versus placebo plus FOLFIRI, in patients with mCRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were required to have ECOG PS 0 or 1 and to have disease progression within 6 months of the last dose of first-line therapy. A total of 1072 patients were randomized (1:1) to receive either CYRAMZA (n=536) at 8 mg/kg as an intravenous infusion or placebo (n=536), in combination with FOLFIRI: irinotecan 180 mg/m² administered intravenously over 90 minutes and folinic acid 400 mg/m² administered intravenously simultaneously over 120 minutes; followed by 5-fluorouracil 400 mg/m² intravenous bolus over 2 to 4 minutes; followed by 5-fluorouracil 2400 mg/m² administered intravenously by continuous infusion over 46 to 48 hours. Treatment cycles on both arms were repeated every 2 weeks. Patients who discontinued one or more components of treatment because of an adverse event were permitted to continue therapy with the other treatment component(s) until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment ( < 6 months versus ≥ 6 months).

Demographic and baseline characteristics were similar between treatment arms. Median age was 62 years; 57% of patients were men; 76% were W hite and 20% Asian; 49% had ECOG PS 0; 49% of patients had KRAS mutant tumors; and 24% of patients had < 6 months from time to disease progression after beginning first-line treatment.

Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA plus FOLFIRI compared to patients randomized to receive placebo plus FOLFIRI. The treatment effect was consistent across the pre-specified stratification factors. Efficacy results are shown in Table 9 and Figure 4.

Table 9: Randomized Trial of CYRAMZA plus FOLFIRI versus Placebo plus FOLFIRI in mCRC

  CYRAMZA + FOLFIRI
N=536
Placebo + FOLFIRI
N=536
Overall Survival
  Number of deaths (%) 372 (69%) 397 (74%)
  Median - months (95% CI) 13.3 (12.4, 14.5) 11.7 (10.8, 12.7)
  Hazard Ratio (95% CI) 0.85 (0.73, 0.98)
  Stratified Log-rank p-value 0.023
Progression-free Survival
  Number of events (%) 476 (89%) 494 (92%)
  Median - months (95% CI) 5.7 (5.5, 6.2) 4.5 (4.2, 5.4)
  Hazard Ratio (95% CI) 0.79 (0.70, 0.90)
  Stratified Log-rank p-value < 0.001
Abbreviations: CI = confidence interval.

Figure 4: Kaplan-Meier Curve of Overall Survival -CYRAMZA plus FOLFIRI versus Placebo plus FOLFIRI in mCRC

Kaplan-Meier Curve of Overall Survival - Illustration

Last reviewed on RxList: 9/14/2015
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.

Health Resources
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations