Neoplasms

All Conditions

Rare Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Gastro-enteropancreatic Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Lanreotide

Antineoplastic Agents, Alkylating

Alkylating Agents

Combination phase for first 6 months: Lanreotide Autogel 120 mg and Temozolomide.

Followed by either 6 months Lanreotide Autogel 120 mg maintenance or 6 months of no treatment.

Lanreotide Autogel 120 mg subcutaneous (s.c) - injection, every 28 days (+/-2 days).

Lanreotide Autogel 120 mg

Temozolomide capsule (variable dose). 150 mg/m2 per day for 5 days in the first month. 200 mg/m2 per day for 5 days in months 2, 3, 4, 5 and 6.

Temozolomide (TMZ)

Ipsen Medical Director

The purpose of the study is to evaluate the efficacy and tolerability of the combination of Lanreotide Autogel 120 mg and Temozolomide in patients with progressive gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) graded as G1 or G2 (G1/G2). All progressive tumours classified according to Response Evaluation Criteria In Solid Tumours (RECIST, 1.1).

Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET

Phase II, Multicentre, Open Label Study to Evaluate the Efficacy of the Combination of Lanreotide Autogel 120mg and Temozolomide in Patients With Progressive Gastro-entero-pancreatic Neuroendocrine Tumours (GEP-NET) G1/G2 - A Pilot-Study

All tumour assessments were performed using the Response Evaluation Criteria In Solid Tumours (RECIST) criteria (1.1). Computer Tomography (CT-scan) or Magnetic Resonance Imaging (MRI) could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at weeks 12, 24 and at early withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression.

The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment and was described in the ITT population along with its 95% Confidence Interval (CI) and was compared to 45% with an exact binomial proportion test. The Last Observation Carried Forward (LOCF) method was used to replace missing assessments at the end of the combination phase.

All tumour assessments were performed using the RECIST criteria (1.1). CT-scan or MRI could be used for as method of tumour measurement and the same method of tumour measurement was used throughout the study for each subject. CT scans/MRI were performed at screening or baseline visit then at baseline, weeks 12, 24, 36, 48 (end of study) and at study withdrawal or at anytime during the study in the case of any clinical or biological signs of tumour progression.

The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months combination treatment followed by either 6 months of lanreotide ATG 120 mg maintenance treatment or no treatment. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test. The LOCF method was used to replace missing assessments at the end of the maintenance phase.

PFS was defined as the time from the date of treatment start to the date of the first documented disease progression or death due to any cause within the first 12 months of treatment. If a subject had not progressed or died after 12 months of treatment or when any further anti-neoplastic therapy was received, PFS was censored at the time of the last tumour assessment before the analysis cut-off date or the anti-neoplastic therapy date.

A Kaplan-Meier estimate of the PFS was calculated to determine the number of subjects at risk. Median PFS time (50% of subjects who would not progress or die) of the ITT population is presented along with 95 % CI.

TtR was defined as the time from the date of treatment start to the date of the first documented objective response (CR or PR) within the first 12 months of treatment (combination and maintenance phases). A Kaplan Meier estimate of the TtR survival function was constructed.

The Kaplan-Meier method was used to estimate the median TtR and its 95% CI for subjects in the ITT population (50% of subjects were expected to have a CR or PR at this time).

The DoR is an estimation of the time from first documented objective response (CR or PR) to the first date of progressive disease (PD) or death due to disease progression for subjects who experienced an objective response within the first 12 months of treatment (combination and maintenance phases).

The Kaplan-Meier method was used to estimate the median DoR and its 95% CI for subjects in the ITT population who had an objective response.

Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 12, 24 and at early withdrawal. The biochemical response after 6 months combination treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 micrograms/litre \[mcg/L\]).

Biochemical response based on CgA levels was categorised as: PR (decrease of CgA ≥ 50%, compared to the baseline CgA), SD (decrease \< 50 % or an increase ≤25%, compared to the baseline CgA) or PD (defined as an increase ≥25 %, compared to the baseline CgA).

The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline.

Blood samples for CgA blood tumour marker analysis were taken at baseline, weeks 12, 24, 36, 48 (end of study) and at early withdrawal. The biochemical response after 12 months combination and maintenance treatment was estimated for subjects with abnormal CgA levels at baseline. Abnormal CgA levels were defined as above the upper limit of normal range (≥100 mcg/L).

Biochemical response based on CgA levels was categorised as: PR (decrease of CgA ≥50 % compared to the baseline CgA), SD (decrease \< 50% or an increase ≤ 25% compared to the baseline CgA) or PD (defined as an increase ≥ 25%, compared to the baseline CgA).

The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population who had abnormal CgA at baseline.

Urine samples for 5-HIAA urinary tumour marker analysis were taken at at baseline, weeks 12, 24and early withdrawal.

Biochemical response based on 5-HIAA levels was categorised as: Response (5-HIAA reduction compared to baseline) or Progression (5-HIAA increase compared to baseline).

The number of subjects in each response category at each time point in the combination phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.

Urine samples for 5-HIAA urinary tumour marker analysis were taken at baseline, weeks 12, 24, 36, 48 (end of study) and early withdrawal.

Biochemical response based on 5-HIAA levels was categorised as: Response (5-HIAA reduction compared to baseline) or Progression (5-HIAA increase compared to baseline).

The number of subjects in each response category at each time point in the maintenance phase is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.

Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline.

Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea / Reduction, Increase or Stability of occurrences of flushing.

The number of subjects in each response category at week 24 (end of the combination phase) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.

Symptomatic response was evaluated as absolute change from baseline in the number of episodes of the lead symptoms (i.e. diarrhoea and flushing) using the mean of the last 3 days before the visit, at each visit, as compared to baseline.

Symptomatic responses were categorised as: Reduction, Increase or Stability of occurrences of diarrhoea / Reduction, Increase or Stability of occurrences of flushing.

The number of subjects in each response category at week 48 (end of study) is presented. Analysis was only carried out on subjects in the ITT population with functioning NET.

Subjects were instructed to complete the QLQ-C30 questionnaire at baseline, weeks 12, 24 or at early withdrawal. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) \& 6 other single items. The last 2 questions represented subject's assessment of overall health \& quality of life, coded on a 7-point scale (1=very poor to 7=excellent). The mean change from baseline at week 24 (end of the combination phase) is presented for global health status (scoring of questions 29 \& 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Each individual subscore was transformed to range from 0 to 100. A higher score represents a higher level response. Thus, a better QoL/a better level of functioning/a worse level of symptoms.

Subjects were instructed to complete QLQ-C30 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) \& 6 other single items. The last 2 questions represented subject's assessment of overall health \& quality of life, coded on a 7-point scale (1=very poor to 7=excellent). The mean change from baseline at week 48 (end of study) is presented for global health status (scoring of questions 29 \& 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Each individual subscore was transformed to range from 0 to 100. A higher score represents a higher level response. Thus, a better QoL/a better level of functioning/a worse level of symptoms.

Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24 or at early withdrawal. It contained 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Each individual subscore was transformed to range from 0 to 100. The mean change from baseline at week 24 (end of combination phase) is presented with a higher score representing a higher level response. Thus, a better level of functioning/a worse level of symptoms.

Subjects were instructed to complete the QLQ-GI.NET21 questionnaire at baseline, weeks 12, 24, 36, 48 (end of study) or at early withdrawal. It contained 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Answers were converted into grading scale, with values between 0 and 100. Each individual subscore was transformed to range from 0 to 100. The mean change from baseline at week 48 (end of study) is presented with a higher score representing a higher level response. Thus, a better level of functioning/a worse level of symptoms.

In all subjects whose tumour tissue was available, MGMT expression/methylation and SSTR expression was analysed. After 6 months, the DCR (SD+PR+CR) by MGMT methylation and expression and by SSTR 2a and SSTR 5 expression was evaluated.

DCR in response to MGMT methylation and expression results are presented. SSTR 2a and SSTR 5 expression is categorised as: No Receptors, Cytoplasmatic Expression (CE), Focal Expression (FE), Complete Circumferent Membrane Expression (CCME).

The DCR was defined as the proportion of subjects with a response of CR, PR or SD after 6 months of combination treatment within each methylation/expression category. The DCR was described in the ITT population along with its 95% CI and was compared to 45% with an exact binomial proportion test.

Lanreotide ATG levels were measured in a subset of subjects to evaluate if temozolomide co-treatment had an impact on lanreotide serum concentration over a 12 month period.

Blood samples were collected for the determination of lanreotide ATG in serum at baseline, weeks 4, 12, 24 and 48 (end of study).

The concentrations of lanreotide ATG in serum were determined by a validated radioimmunoassay analysis method with a lower limit of quantitation of 0.08 nanograms \[ng\]/mL).

Serum concentrations of lanreotide ATG at each of the time points in the combination and maintenance phase are presented. Only subjects with data available for analysis are presented.

Ipsen

Treatment Emergent Adverse Events (TEAEs) are reported for both the combination and maintenance phases and include events with an onset after the start of study drug treatment to the last intake of study drug plus 28 days.

All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months.

Subjects received 1 injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 day treatment cycle. The temozolomide dose was adapted to the subject body surface area (BSA) and the dose in the 1st treatment cycle was 150 mg/metres squared (m\^2) per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m\^2 per day from cycle 2 to cycle 6.

Combination Phase

In case of clinical benefit, defined as either CR, PR or SD, after the first 6 months combination phase all subjects with functioning NET continued to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

Maintenance Phase - Functioning NET, Lanreotide

Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to continue to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

Maintenance Phase - Non-functioning NET, Lanreotide

Following completion of the 6-month combination phase, all subjects with non-functioning NET and clinical benefit were randomised to receive no treatment for 6 months. This maintenance phase started with visit 8, week 24.

Maintenance Phase - Non-functioning NET, No Treatment

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Medical Director

The ITT population is all subjects that had at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

Disease Control Rate (DCR) After 6 Months

In case of clinical benefit, defined as either complete response (CR), partial response (PR) or stable disease (SD) after the first 6 months combination phase, all subjects with functioning (serotonin producing) NET continued to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

After the first 6 months combination phase, subjects with non-functioning NET and clinical benefit were randomised to continue to receive lanreotide ATG 120 mg for another 6 months. This maintenance phase started with visit 8, week 24.

After the first 6 months combination phase, subjects with non-functioning NET and clinical benefit were randomised to receive no treatment for 6 months. This maintenance phase started with visit 8, week 24.

DCR After 12 Months

All treated subjects having at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

Intention-to-treat (ITT) Population

The ITT population is all treated subjects that had at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

Progression-Free Survival (PFS) Within 12 Months

The ITT population is all treated subjects having at least one baseline and at least one post baseline assessment of the primary efficacy parameter

Time To Response (TtR) Within 12 Months

The ITT population is all treated subjects having at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

Duration of Response (DoR) Within 12 Months

Week 12- PD

Week 12 - SD

Week 12- PR

Week 12 - Missing

Week 24 - PD

Week 24 - SD

Week 24 - PR

Week 24 - Missing

Early Withdrawal - PD

Early Withdrawal - SD

Early Withdrawal - PR

Early Withdrawal - Missing

Subjects in the ITT population with abnormal CgA levels at baseline.

The Number of Subjects With a Biochemical Response Using Chromogranin-A (CgA) Levels After 6 Months

Week 36 - PD

Week 36 - SD

Week 36 - PR

Week 36 - Missing

Week 48 - PD

Week 48 - SD

Week 48 - PR

Week 48 - Missing

The Number of Subjects With a Biochemical Response Using CgA Levels After 12 Months

Week 12 - Progression

Week 12 - Response

Week 12 - Not evaluable

Week 24 - Progression

Week 24 - Response

Week 24 - Not evaluable

Early Withdrawal - Progression

Early Withdrawal - Response

Early Withdrawal - Not Evaluable

All subjects in the combination phase who were categorised at baseline as having functioning NET.

Combination Phase - Functioning NET

Subjects in the ITT population with functioning NET.

The Number of Subjects With a Biochemical Response Using 5-Hydroxy-Indol-Amino-Acid (HIAA) Levels After 6 Months

Week 36 - Progression

Week 36 - Response

Week 36 - Not evaluable

Week 48 - Progression

Week 48 - Response

Week 48 - Not evaluable

Early Withdrawal - Not evaluable

The Number of Subjects With a Biochemical Response Using 5-HIAA Levels After 12 Months

Diarrhoea - Reduction

Diarrhoea - Increase

Diarrhoea - Stability

Diarrhoea - Missing

Flushing - Reduction

Flushing - Increase

Flushing - Stability

Flushing - Missing

The Number of Subjects With a Symptomatic Response After 6 Months

The Number of Subjects With a Symptomatic Response After 12 Months - Maintenance Phase

Global health status

Physical functioning

Role functioning

Emotional functioning

Cognitive functioning

Social functioning

Fatigue

Nausea and vomiting

Pain

Dyspnoea

Insomnia

Appetite loss

Constipation

Diarrhoea

Financial difficulties

Only subjects in the ITT Population with data available at the week 24 time point were analysed. Only subjects with data available for analysis are presented.

European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Core 30 Questionnaire (QLQ-C30): Mean Change From Baseline at 6 Months

Only subjects in the ITT Population with data available at the week 48 time point were analysed. Only subjects with data available for analysis are presented.

EORTC QoL Questionnaire QLQ-C30: Mean Change From Baseline at 12 Months

Endocrine symptoms

Gastrointestinal (G.I.) symptoms

Treatment related symptoms

Social function

Disease related worries

Muscle/bone pain symptoms

Body image

Weight gain

Information/communication function

Sexual function

Quality of Life Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21): Mean Change From Baseline at 6 Months

G.I. symptoms

QoL Questionnaire QLQ-GI.NET21: Mean Change From Baseline at 12 Months

MGMT Methylation

MGMT No methylation

MGMT Expression

MGMT No expression

SSTR 2a No Receptors

SSTR 2a CE

SSTR 2a FE

SSTR 2a CCME

SSTR 5 - No Receptors

SSTR 5 CE

SSTR 5 FE

SSTR 5 CCME

All subjects received lanreotide ATG 120 mg plus temozolomide in combination for 6 months.

Subjects received 1 injection of lanreotide ATG 120 mg and temozolomide capsules for 5 consecutive days, in a 28 day treatment cycle. The temozolomide dose was adapted to the subject body surface area (BSA) and the dose in the 1st treatment cycle was 150 mg/metres squared (m\^2) per day. Depending on the safety laboratory values, the temozolomide dose was increased to 200 mg/m\^2 per day from cycle 2 to cycle 6

Percentages are based on the number of subjects in the ITT population and with data available for analysis.

DCR by O6-methylguanine-DNA Methyl-transferase (MGMT) Expression and Methylation and Somatostatin Receptor (SSTR) Expression After 6 Months

Baseline

Week 4

Week 12

Week 24

Week 48

All subjects for whom PK assessments were performed and with evaluable PK data.

PK Subset

PK analysis was performed using the valid PK population.

Spots Global Cancer Trial Database for Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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