CLARINET Study

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Caplin ME, et al. "Lanreotide in metastatic enteropancreatic neuroendocrine tumors". New England Journal of Medicine. 2014. 371(3):224-233.
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Bottom Line

Major Points

Guidelines

Design

  • Phase III, multicentre, randomized, double-blind placebo-controlled trial
  • N=204
    • Lanreotide (n=101)
    • Placebo (n=103)
  • Setting: 48 sites in 14 countries
  • Enrollment: 2006-2013
  • Screening 12-24w; CT/MRI between that period x2
  • Analysis: Intention-to-treat
  • Primary outcome: PFS

Population

Inclusion Criteria

  • Adults (≥18 years of age) with sporadic neuroendocrine tumors
  • Confirmed centrally to be well differentiated or moderately differentiated and measurable
  • Tumors had a centrally assessed proliferation index (Ki-67 antigen < 10%)
  • Primary tumors in the pancreas, midgut, or hindgut or were of unknown origin.
  • Tumors were nonfunctioning, except for gastrinomas adequately treated
  • Unresectable locally advanced tumor or metastatic disease (or the patient declined surgery), target lesion/s that were classified on somatostatin-receptor scintigraphy as grade 2 or higher

Exclusion Criteria

  • Treatment with IFN, chemoembolization, or chemotherapy within 6 months before study entry,
  • Radionuclide at any time, or a somatostatin analogue at any time
  • Major surgery related to the neuroendocrine tumor within 3 months before study entry
  • Multiple endocrine neoplasia
  • Previous cancer (except treated or untreated in situ cervical or uterine carcinoma or basal-cell skin carcinoma or patients with other cancers who had been treated with curative intent and had been disease-free for >5 years)

Baseline Characteristics

Baseline Characteristics All data for lanreotide vs placebo

  • Males: 52% vs 52%
  • Age: 63.3+/-9.8 vs 62.2+/-11.1
  • Time since diagnosis: 32.6+/-46.1 vs 34.4+/-41.4
  • Prior treatment for NET: 16% vs 16%
  • Primary tumour resected: 40% vs 38%
  • Origin of NET Pancreas: 42% vs 48%
  • Origin of NET Midgut: 33% vs 39%
  • Origin of NET Hindgut: 11% vs 3%
  • Origin of NET Unknown/Other: 15% vs 11%
  • Tumour progression: 4% vs 5%
  • Tumour grade Ki-67 0-2%: 68% vs 70%
  • Tumour grade Ki-67 3-10%: 32% vs 28%
  • Tumour grade data missing: 0% vs 2%

Interventions

  • Extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot]), at a dose of 120 mg, or placebo (sodium chloride) was administered, without dose adjustment, by means of deep subcutaneous injection every 28 days (to a maximum of 24 injections).
  • Study visits were scheduled during the screening period and at weeks 1 (baseline), 12, 24, 36, 48, 72, and 96.
  • Single scans were obtained at all post-baseline visits. 

Outcomes

Comparisons are lanrotide vs. placebo

Primary Outcomes

  • PFS was significantly prolonged with lanreotide vs placebo in the primary analysis
  • Median PFS, not reached vs. 18.0 months, P<0.001 stratified log-rank test;
  • HR for progression / death, 0.47; 95% confidence interval [CI], 0.30 to 0.73, p=0.0002

Secondary Outcomes

  • Patients alive without disease progression wk 48 - (%): 66% vs 49% (OR 2.11 95%CI 1.19 to 3.76), P<0.05, NNT=5.9)
  • Patients alive without disease progression wk 96 - (%): 52% vs 25% (OR 3.27 95%CI 1.81 to 5.93), P<0.001, NNT=3.7)
  • Overall survival: 19 vs 17 deaths not signifcant
  • Median TTP: Not reached vs 18m (12.1-24)m
  • EORTC QLQ-C30 Global HS Score: −5.18±3.73 vs −4.87±3.7 Least squares mean difference −0.31±2.74 (−5.73 to 5.10)
  • Patients with ≥50% reduction in level of chromogranin A from baseline to last post-baseline level available (%): 42% vs 5% (OR 15.20 95% CI 4.29 to 53.87, P<0.001, NTT=2.7)

Subgroup Analysis

Adverse Events

  • Any adverse event: 88% vs. 90%
  • Any adverse event related to study treatment: 50% vs. 28%
  • Any adverse event according to intensity
    • Severe: 26% vs. 31%
    • Moderate: 44% vs. 43%
    • Mild: 17% vs. 17%
  • Any serious adverse event: 25% vs. 31%
  • Serious adverse event related to study treatment: 3% vs. 1%
  • Withdrawal from study because of any adverse event: 3% vs. 3%
  • Withdrawal because of adverse event related to study treatment: 1% vs. 0%

Criticisms

Funding

Further Reading