A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC) (PROTECT)

Novartis

Status and phase: Completed; Phase 3

Conditions: Renal Cell Carcinoma (RCC); Cancer

Treatments: Drug: pazopanib; Drug: placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01235962

2010-020965-26 (EudraCT Number)

113387

CPZP034D2301 (Other Identifier)

Details and patient eligibility

About

This randomized Phase III study is to evaluate whether pazopanib compared with placebo can prevent or delay recurrence of kidney cancer in patients with moderately high or high risk of developing recurrence after undergoing kidney cancer surgery.

Full description

The primary objective of this ongoing study was to evaluate DFS with pazopanib 600 mg daily initial dose as compared with placebo as adjuvant therapy for subjects with localized/locally advanced RCC following nephrectomy.

Subjects with locally recurrent renal cell carcinoma (RCC), bilateral RCC, or history of another malignancy were excluded from enrolling in the study.

The study was comprised of three successive study periods: 1) the Screening/Baseline period, 2) the study treatment period, and 3) the DFS /OS follow-up period. The Screening/Baseline period had a maximum duration of 12 weeks from the date of nephrectomy to the date of randomization.

After a subject met all the eligibility criteria and completed all the required baseline assessments, the subject was randomized in a 1:1 ratio to receive once daily blinded treatment with either pazopanib 600 mg as initial dose or matching placebo based on pre-defined stratification factors.

Subjects received continuous daily treatment until completion of the 12-month treatment period, disease recurrence, or unacceptable toxicity/intolerance. Subsequent adjuvant therapies for RCC were not allowed. During the study treatment and DFS follow-up periods, subjects received routine safety and efficacy assessments.

The study treatment period was 12 months. Subjects received continuous daily treatment until completion of the 12 month treatment period, disease recurrence, or unacceptable toxicity/intolerance. Subsequent adjuvant therapies for RCC were not allowed.

All subjects, regardless of study treatment status (i.e. premature discontinuation or completion of the 12-month treatment), were to be followed with routine imaging assessments and remain blinded until objective evidence of disease recurrence was obtained or until the study achieved the required number of events for the primary endpoint of DFS (319 events). After objective evidence of disease recurrence was obtained, subjects could be unblinded and received the first-line treatment for metastatic RCC per local standard of care.

All subjects were off treatment for at least 4 years at the end of study.

Enrollment: 1,538 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Signed written informed consent

• Diagnosis of RCC with clear-cell or predominant clear-cell histology

• Subjects with non-metastatic disease (M0) fulfilling any of the following combinations of pathologic staging based on American Joint Committee on Cancer (AJCC) TNM staging version 2010 and Fuhrman nuclear grading.

  • pT2, G3 or G4, N0; or,
  • pT3, G any, N0; or,
  • pT4, G any, N0; or,
  • pT any, G any, N1

• Fulfill all of the following criteria of disease-free status at baseline:

  • Had complete gross surgical resection of all RCC via radical or partial nephrectomy using either open or laparoscopic technique.
  • Baseline imaging of chest, abdomen and pelvis shows no metastasis or residual tumor lesions as confirmed centrally by an independent radiologist.

• Received no prior adjuvant or neo-adjuvant treatment for RCC

• Recovered from nephrectomy: any surgery related toxicities should be reduced to ≤ grade 1 per NCI Common Terminology Criteria for Adverse Events (CTCAE) (Version 4)

• Karnofsky performance scale (KPS) of ≥ 80

• Adequate organ system function

Exclusion criteria

• History of another malignancy. Exception: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible

• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

  • Active peptic ulcer disease
  • Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment

• Active diarrhea of any grade

• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:

  • Malabsorption syndrome
  • Major resection of the stomach or small bowel

• History of human immunodeficiency virus (HIV) infection

• History of active hepatitis

• Presence of uncontrolled infection.

• History of any one or more of the following cardiovascular conditions within the past 6 months:

  • Cardiac angioplasty or stenting
  • Myocardial infarction
  • Unstable angina
  • Coronary artery bypass graft surgery
  • Symptomatic peripheral vascular disease

• History of Class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart Failure

• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

• Corrected QT interval (QTc) > 480 milliseconds (msec)

• Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study (see Section 7.6.2 for instruction on blood pressure measurement and obtaining mean blood pressure values).

• Evidence of active bleeding or bleeding diathesis
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
• Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study treatment and for the duration of the study.
• Concurrent therapy given to treat cancer including treatment with an investigational agent or concurrent participation in another clinical trial involving anti-cancer investigational drug.
• Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or excipients that in the opinion of the investigator contraindicates their participation.
• Prior or current use of systemic anti-VEGF inhibitors, cytokines (e.g. interferon, interleukin 2).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,538 participants in 2 patient groups, including a placebo group

pazopanib

Experimental group

Description:

Pazopanib oral agent, administered at 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months. Dose can be reduced, interrupted or discontinued due to adverse events or intolerance.

Treatment:

Drug: pazopanib

Drug: pazopanib

placebo

Placebo Comparator group

Description:

placebo matching pazopanib 200 mg tablets, administered at 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months. Dose can be reduced, interrupted or discontinued due to adverse events or intolerance.

Treatment:

Drug: placebo

Drug: placebo