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Wilke H et al. Lancet Oncol. 2014;15:1224–1235

Supplement to: Wilke H et al. Lancet Oncol. 2014;15:1224–1235

FDA and EMA prescribing information and miscellaneous sources

 

Prophylaxis for infusion-related reaction from ramucirumab

Diphenhydramine 50 mg; administer intravenously, 30–60 minutes before each ramucirumab dose (note diphenhydramine is also indicated for prophylaxis with paclitaxel, as described below), plus

Acetaminophen 650–1000 mg; administer orally, 30–60 minutes before ramucirumab (only if history of grade 1/2 infusion reaction), plus

Dexamethasone 8 mg; administer orally or intravenously, 30–60 minutes before ramucirumab (only if history of grade 1/2 infusion reaction; note dexamethasone is also indicated for prophylaxis with paclitaxel, as described below)

 

Ramucirumab 8 mg/kg per dose; administer intravenously in 250 mL of 0.9% sodium chloride injection (0.9% NS) over 1 hour for 2 doses on days 1 and 15, prior to paclitaxel, every 28 days, until disease progression (total dosage/28-day cycle = 16 mg/kg)

  • Administration of ramucirumab with an administration set that contains a low protein-binding in-line or add-on filter with pore size of 0.22 μm is recommended

  • Flush the line with 0.9% NS following completion of the ramucirumab infusion

 

Prophylaxis for infusion-related reaction from paclitaxel:

 

Diphenhydramine 50 mg; administer intravenously 30–60 minutes before each paclitaxel dose (note diphenhydramine is also indicated for prophylaxis with ramucirumab, as described above), plus:

Dexamethasone 10 mg; administer intravenously 30–60 minutes before each paclitaxel dose, plus:

Cimetidine 300 mg (or ranitidine 50 mg, or famotidine 20 mg, or an equivalent histamine receptor [H2]-subtype antagonist); administer intravenously over 15–30 minutes, 30– 60 minutes before each paclitaxel dose

 

Paclitaxel 80 mg/m2 per dose; administer intravenously in a volume of 0.9% NS or 5% dextrose injection (D5W) sufficient to produce a concentration within the range 0.3–1.2 mg/mL over 1 hour for 3 doses on day 1, 8, and 15, every 28 days, until disease progression (total dosage/28-day cycle = 240 mg/m2)

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1, 8, and 15 is LOW

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

 

Patient Population Studied

An international, multicenter, randomized, placebo-controlled, double-blind, phase 3 trial (RAINBOW) involved 665 patients with metastatic or nonresectable, locally advanced gastric or gastroesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum and fluoropyrimidine doublet with or without anthracycline). Eligible patients were aged ≥18 years and had Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. Patients with squamous or undifferentiated gastric cancer; gastrointestinal perforation, fistulae, or any arterial thromboembolic event within 6 months before randomization; any significant bleeding or any significant venous thromboembolism within 3 months before randomization; or poorly controlled hypertension were ineligible. Patients were randomly assigned (1:1) to receive 28-day cycles of intravenous ramucirumab (8 mg/kg on days 1 and 15) and paclitaxel (80 mg/m2 on days 1, 8, and 15) or placebo (on days 1 and 15) and paclitaxel (80 mg/m2 on days 1, 8, and 15).

Efficacy (N = 665)

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Efficacy (N = 665)
  Ramucirumab and Paclitaxel (N = 330) Placebo and Paclitaxel (N = 335)  
Median overall survival 9.6 months 7.4 months HR 0.807, 95% CI 0.678–0.962; P = 0.017
Median progression-free survival 4.4 months 2.9 months HR 0.635, 95% CI 0.536–0.752; P <0.0001
Objective response rate 28% 16% P = 0.0001
Disease control rate 80% 64% P <0.0001

Objective response rate included patients with complete or partial response, as assessed by investigators according to RECIST version 1.1

Disease control rate included complete response, partial response, or stable disease

Note: Median duration of follow-up was 7.9 months

Therapy Monitoring

  1. Before the start of a cycle: CBC with differential, serum electrolytes, BUN, creatinine, bilirubin, AST or ALT, and alkaline phosphatase

  2. Once per week: CBC with differential and platelet count

  3. Blood pressure every 2 weeks or more frequently as indicated during treatment

  4. Prior to each dose of ramucirumab: Assess proteinuria by urine dipstick and/or urinary protein creatinine ratio. Patients with a urine dipstick reading ≥2+ should undergo further assessment with a 24-hour urine collection

  5. Observe closely for hypersensitivity reactions, especially during the first and second infusions

  6. Every 2–3 months: Imaging to assess response

Treatment Modifications

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Treatment Modifications
RAMUCIRUMAB DOSAGE MODIFICATIONS
Starting dose 8 mg/kg
Dose level −1 6 mg/kg
Dose level −2 5 mg/kg
 
Adverse Event Treatment Modification
G1/2 infusion-related Stop ramucirumab. Administer dexamethasone intravenously at commonly used antiemetic dosages of 8–20 mg (or equivalent) and acetaminophen, then resume infusion at 50% of previous rate. Use the 50% infusion rate for all subsequent administrations
Prior G1/2 infusion-related reaction Premedicate with dexamethasone intravenously at commonly used antiemetic dosages of 8–20 mg (or equivalent), acetaminophen, and diphenhydramine 50 mg intravenously prior to each subsequent ramucirumab infusion
G3/4 infusion-related reaction Permanently discontinue ramucirumab
G3/4 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg; medical intervention indicated; >1 drug or more intensive therapy than previously used indicated; or worse) Interrupt ramucirumab until controlled with medical management, then resume ramucirumab; if unable to control with medical management, discontinue ramucirumab
Reversible posterior leukoencephalopathy syndrome (RPLS) Permanently discontinue ramucirumab
Urine protein ≥2 g/24 h Interrupt ramucirumab. Reinitiate treatment reduced by 1 dose level once the urine protein level returns to <2 g/24 h
Reoccurrence of urine protein ≥2 g/24 h Interrupt ramucirumab. Reinitiate treatment reduced by 1 dose level once the urine protein level returns to <2 g/24 h
Urine protein >3 g/24 h or nephrotic syndrome Permanently discontinue ramucirumab
Anticipated wound healing Stop ramucirumab ≥4 weeks prior to a scheduled surgery until wound is fully healed; discontinue ramucirumab if patient develops wound healing complications
G3/4 bleeding, arterial thromboembolic event, gastrointestinal perforation Permanently discontinue ramucirumab
G3/4 fatigue/asthenia Interrupt ramucirumab. Reinstitute treatment at a reduced dose once toxicity is G1
G3/4 stomatitis/mucosal inflammation
   
WEEKLY PACLITAXEL DOSAGE MODIFICATIONS
Paclitaxel starting dose  80 mg/m2
Paclitaxel dose level −1  70 mg/m2
Paclitaxel dose level −2  60 mg/m2
Adverse Event Treatment Modifications
Febrile neutropenia (ANC <1000/mm3 with temperature >38°C or >100.4°F), or ANC <1000/mm3 for ≥7 days Reduce paclitaxel dose by 10 mg/m2 and consider adding filgrastim in subsequent cycles, if applicable
Febrile neutropenia (ANC <1000/mm3 with temperature >38°C or >100.4°F), or ANC <1000/mm3 for ≥7 days despite dosage reduction of 10 mg/m2 Administer filgrastim in subsequent cycles. If already administering filgrastim, reduce paclitaxel dose an additional 10 mg/m2
Platelet nadir <50,000/mm3, or platelets <100,000/mm3 for ≥7 days Reduce paclitaxel dose by 1 level
ANC <800/mm3 or platelets <50,000/mm3 at the start of a cycle Hold treatment until ANC >800/mm3 and platelets >50,000/mm3, then resume with weekly paclitaxel dosage reduced by 10 mg/m2
G2 motor or sensory neuropathies Reduce weekly paclitaxel dosage by 10 mg/m2 without interrupting planned treatment
Other nonhematologic adverse events G2/3 Hold treatment until adverse events resolve to <G1, then resume with weekly paclitaxel dosage reduced by 10 mg/m2
Patients who cannot tolerate paclitaxel at 60 mg/m2 per week Discontinue treatment
Treatment delay >2 weeks Decrease weekly paclitaxel dosage by 10 mg/m2 or consider discontinuing treatment

Adverse Events (N = 656)

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Adverse Events (N = 656)
  Ramucirumab and Paclitaxel (N = 327) Placebo and Paclitaxel (N = 329)
Grade (%) Grade 1/2 Grade ≥3 Grade 1/2 Grade ≥3
Fatigue 45 12 38 5
Neutropenia 14 41 12 19
Neuropathy 38 8 32 5
Decreased appetite 37 3 28 4
Abdominal pain 30 6 26 3
Nausea 33 2 30 2
Anemia 26 9 26 10
Leukopenia 17 17 14 7
Alopecia 33 0 38 <1
Diarrhea 29 4 22 2
Epistaxis 31 0 7 0
Vomiting 24 3 17 4
Peripheral edema 24 2 13 <1
Hypertension 10 14 2 2
Constipation 21 0 21 <1
Stomatitis 19 <1 7 <1
Pyrexia 17 <1 11 <1
Proteinurea 15 1 6 0
Malignant neoplasm progression 2 14 <1 18
Weight decreased 12 2 14 1
Thrombocytopenia 12 2 4 2
Rash 13 0 9 0
Dyspnea 10 2 9 <1
Cough 12 0 8 0
Back pain 11 1 11 2
Hypoalbuminemia 10 1 4 <1
Ascites 6 4 4 4
Myalgia 10 0 10 <1
Headache 10 0 6 <1

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.02

Notes: Treatment-emergent toxicities that occurred in ≥10% of patients in the ramucirumab plus paclitaxel group are included in the table, irrespective of causality. Treatment-emergent adverse events leading to death occurred in 12% of the ramucirumab plus paclitaxel group and 16% of the placebo plus paclitaxel group; in each group, 2% of patients experienced an adverse event leading to death with a causal relation to any study drug

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