Pasireotide LAR and Pegvisomant Study in Acromegaly (PAPE)

Efficacy and Safety of Pasireotide Long Acting Release (LAR) in Combination With Weekly Pegvisomant in Previously Controlled Acromegaly Patients on Combination Treatment of Long-Acting Somatostatin Analogues and Weekly Pegvisomant

The objective of this study is to assess the efficacy of Pasireotide Long Acting Release (LAR) alone and in combination with weekly Pegvisomant (PEGV) in acromegaIy patients previously controlled with combination treatment of long-acting Somatostatin analogs (LA-SSAs) and PEGV.

Study Overview

• Status: Unknown
• Conditions: Acromegaly
• Intervention / Treatment: Drug: Pasireotide LAR 60 mg; Drug: Pegvisomant

Detailed Description

Pasireotide Long Acting Release (Signifor ®), a novel long-acting multi-receptor ligand somatostatin analogue, has been shown to be more effective for the treatment of GH-secreting pituitary adenomas than currently used long-acting somatostatin analogues (LA-SSAs). The long-term efficacy of acromegaly patients using LA-SSAs in combination with PEGV was over 90% in terms of normalization of IGF-I. The combination of PEGV with pasireotide LAR has not been studied yet. Combining PEGV with pasireotide LAR could result in a lower dose and less injections of pegvisomant. This may ultimately lead to a more cost-effective treatment and improved quality of life.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3000CA
      • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• written informed consent male or female aged ≥ 18 years
• documentation supporting the diagnosis of acromegaly based on elevated GH and/or IGF-I levels due to a pituitary tumor
• the patient is treated with lanreotide Autogel or octreotide LAR and PEGV (twice) weekly for at least 6 months and has a serum IGF-I level within 120 % of the age adjusted normal limits. These patients were previously not controlled by somatostatin analogs alone.
• female of no childbearing potential or male. No childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired) or using two acceptable contraceptive measures, except for oral contraceptives.
• male subjects must agree that, if their partner is at risk of becoming pregnant, they will use a medically accepted, effective method of contraception (i.e. use a condom) for the duration of the study
• subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

Patients will not be included in the study if he or she:

• has undergone pituitary surgery or radiotherapy within 6 months prior to study entry.
• it is anticipated that the patient will receive pituitary surgery or radiotherapy during the study.
• has a history of hypersensitivity to lanreotide, octreotide or pegvisomant or drugs with a similar chemical structure
• has been treated with any unlicensed drug within the last 30 days before study entry.
• has abnormal hepatic function at study entry (defined as AST, ALT, gGT, alkaline phosphatase, or total bilirubin above 3 ULN)
• is at risk of pregnancy or is lactating. Females of childbearing potential must provide a negative pregnancy test within 5 days before the start of the study and must be using contraception. Non-childbearing potential is defined as post-menopause for at least one year, surgical sterilization or hysterectomy at least three months before the start of the study.
• has a history of, or known current problems with alcohol or drug abuse.
• has a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
• has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.
• renal insufficiency, clearance < 50ml/min
• poorly controlled diabetes mellitus with an HbA1c > 9.0%
• patients with a QTc > 500 ms on the EKG
• participation in a clinical trial in the last 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pasireotide LAR 60 mg monotherapy week 12; After enrollment, acromegaly patients on combination treatment will half their regular weekly dose of pegvisomant (PEGV) for 12 weeks (run-in period). When insuline-like growth factor 1 (IGF-I) remains within the age adjusted normal limits after 12 weeks, PEGV and the LA-SSA (Octreotide Long Acting Release (LAR) or Lanreotide Autogel) with Pegvisomant (PEGV) are discontinued and patients are switched to pasireotide LAR 60 mg for 12 weeks.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Names: Signifor, SOM230
EXPERIMENTAL: Pasireotide LAR 60 mg and Pegvisomant week 12; When IGF-I rises above the adjusted normal limits after 12 weeks (run-in period), these subjects will switch their LA-SSA to Pasireotide LAR 60 mg every 4 weeks and continue with the reduced PEGV dose of the run-in period, for the remaining 12 weeks.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Names: Signifor, SOM230; Drug: Pegvisomant; only in combination with pasireotide LAR; Other Names: Somavert
EXPERIMENTAL: Pasireotide LAR 60 mg and Pegvisomant week 24; Between week 12 and 24 dose adaptations of PEGV are not permitted unless IGF-I drops below the age adjusted normal limits, then the dose of PEGV will be decreased stepwise with 20 mg weekly until IGF-I is within the age adjusted normal limits. At week 24, efficacy will be assessed, as the number of patients with a normal IGF-I in the two different groups; the combination Pasireotide LAR 60 mg / PEG V dose and monotherapy Pasireotide LAR 60 mg. From week 24 patients will continue with Pasireotide LAR 60 mg monotherapy, or Pasireotide LAR will be combined with 50% of the original dose of PEGV, or with an increasing dose of PEGV every 8 weeks depending on the treatment arm.	Drug: Pasireotide LAR 60 mg; as mono-therapy or in combination with pegvisomant; Other Names: Signifor, SOM230; Drug: Pegvisomant; only in combination with pasireotide LAR; Other Names: Somavert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The proportion of patients with normalized IGF1 levels at 24 weeks in the pasireotide LAR monotherapy group and in the pasireotide LAR combined with pegvisomant group	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of patients with normalized IGF1 levels after 48 weeks of pasireotide LAR monotherapy		48 weeks
The proportion of patients with normalized IGF1 levels after 48 weeks combination treatment of pasireotide LAR with weekly pegvisomant.		48 weeks
The necessary dose of pegvisomant during combination treatment of pasireotide LAR with pegvisomant in patients with an IGF-I level within the age adjusted normal limits		48 weeks
Change in tumor volume by pituitary MRI		Baseline and 48 weeks
Tolerability and safety profile of pasireotide Long Acting Release (LAR) monotherapy	Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed from study enrollment until the safety follow-up.	48 weeks
Tolerability and safety profile of pasireotide LAR and pegvisomant combination therapy	Toxicity will be assessed using the National Cancer Institute-Common Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4.03) and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose, insulin, HbA1c, and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/Significant nondrug therapies will be assessed from study enrollment until the safety follow-up.	48 weeks
Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly	AcroQol is quality of life questionnaire specifically designed for acromegaly	Change in scores as measured by AcroQoL from baseline to week 48
Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly	PASQ are questionnaire for the disease specific symptoms	Change in scores as measured by PASQ from baseline to week 48
Evaluation of long term effect of pasireotide LAR with or without pegvisomant on AcroQol, PASQ and signs and symptoms of acromegaly		Description of signs and symptoms of acromegaly
Evaluation of body composition by Dual-energy X-ray Absorptiometry (DEXA) scan		baseline and 48 weeks

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Novartis
• Investigators: Principal Investigator: Sebastian Neggers, MD PhD, Erasmus Medical Center

Publications and helpful links

General Publications

• Muhammad A, van der Lely AJ, Delhanty PJD, Dallenga AHG, Haitsma IK, Janssen JAMJL, Neggers SJCMM. Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Controlled With Pegvisomant and First-Generation Somatostatin Analogues (PAPE Study). J Clin Endocrinol Metab. 2018 Feb 1;103(2):586-595. doi: 10.1210/jc.2017-02017.

Helpful Links

• Summary of study at the WHO International Clinical Trials Registry Platform

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (ANTICIPATED): March 1, 2017
• Study Completion (ANTICIPATED): June 1, 2017

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: January 26, 2016
• First Posted (ESTIMATE): January 29, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): August 3, 2016
• Last Update Submitted That Met QC Criteria: August 2, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: pasireotide LAR; pegvisomant; long acting somatostatin analogues
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pasireotide
• Other Study ID Numbers: NL49517.078.14; 2014-002219-41 (EUDRACT_NUMBER); NTR5282 (REGISTRY: Dutch Trial Register)