Neurofibromatosis 1, Plexiform Neurofibroma (PN)
Conditions
Keywords
Neurofibromatosis Type 1, NF1, Plexiform Neurofibroma (PN), PNs, Selumetinib, MEK inhibitor
Brief summary
A global study to demonstrate the effectiveness of selumetinib in participants with NF1 who have symptomatic, inoperable plexiform neurofibromas.
Detailed description
This is a randomized, double-blind, placebo-controlled, 2 arm multicentre, global Phase III study to assess the efficacy and safety of selumetinib compared with placebo in adult participants with NF1 who have symptomatic, inoperable PN.
Interventions
DRUGSelumetinib
Selumetinib oral capsules (10 mg and 25 mg)
OTHERPlacebo
Placebo oral capsules for Selumetinib masking (10 mg and 25 mg)
Sponsors
AstraZeneca
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults ≥ 18 years at enrollment with diagnosis of NF1 with symptomatic, inoperable PN * At least one inoperable target PN measurable by volumetric MRI analysis * Chronic target PN pain score documented for minimum period during screening period * Stable chronic PN pain medication use at enrollment * Adequate organ and marrow function Key
Exclusion criteria
* Confirmed or suspected malignant glioma or MPNST (low grade glioma, including optic glioma not requiring systemic therapy or radiation therapy are exempt from this exclusion) * History of malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence * Clinically significant cardiovascular disease, including inherited coronary disease, acute coronary syndrome within 6 months prior to enrollment, uncontrolled angina, symptomatic heart failure, cardiomyopathy, severe valvular heart disease, abnormal LVEF and uncontrolled hypertension * Ophthalmological findings/conditions including intraocular pressure \> 21 mmHg, RPED/CSR or RVO * Prior exposure to MEK inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Partial and Complete Response Rate (ORR) by End of Cycle 16 Using Volumetric MRI Analysis as Determined by ICR (Per REiNS Criteria) in Participants With NF1 Who Have Symptomatic, Inoperable PN. | From first dose up until progression (if it occurs prior to the end of Cycle 16), or the last evaluable assessment up to and including the end of Cycle 16, excluding MRI during prolonged study intervention interruption (defined as interruption >= 28 days) | Objective response rate is defined as the proportion of participants who have a confirmed CR (defined as disappearance of the target PN, confirmed by a consecutive scan within 3 to 6 months after the first response) or confirmed PR (defined as a target PN volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3 to 6 months after the first response) by end of Cycle 16 as determined by ICR per REiNS criteria. Increase in the volume of the target PN by 20% or more compared to baseline or the time of best response after documenting a PR is considered as PD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Primary Analysis | Baseline and end of cycle 12 of study intervention | The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo in participants with a PAINS-pNF chronic target PN pain score of ≥ 3 at baseline is presented. |
| (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Supplemental Analysis | Baseline and end of cycle 12 of study intervention | The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo participants is presented. |
| (Second Key Secondary Endpoint) The Difference of the Means in the Change From Baseline in PlexiQoL Total Score at Cycle 12 | Baseline and end of Cycle 12 of study intervention | PlexiQoL (Plexiform Neurofibroma Quality of Life scale) is a patient-derived QoL measure specific to adults with NF1-associated PNs. It assesses the impact of PNs on patients' ability to fulfil their human needs. The measure consists of 18 dichotomous items with 0 =Not True and 1 = True. PlexiQoL total scores were calculated by the sum of all items to a maximum of 18, with lower scores indicating better quality of life. The change from baseline to the end of each cycle in PlexiQoL total score was derived as the PlexiQoL total score at the cycle 12 minus baseline PlexiQoL total score and presented. |
Countries
Australia, Brazil, Canada, China, France, Germany, Italy, Japan, Poland, Russia, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORAlice P. Chen, MD
National Cancer Institute (NCI)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib 25 mg/m2 Actual Treatment Group | 71 |
| Placebo Actual Treatment Group | 74 |
| Total | 145 |
Baseline characteristics
| Characteristic | Selumetinib 25 mg/m2 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 32.6 Years STANDARD_DEVIATION 11.42 | 29.8 Years STANDARD_DEVIATION 8.72 | 31.2 Years STANDARD_DEVIATION 10.19 |
| Baseline PAINS-pNF chronic target PN pain intensity score Baseline PAINS-pNF chronic target PN pain intensity score < 3 | 21 Participants | 21 Participants | 42 Participants |
| Baseline PAINS-pNF chronic target PN pain intensity score Baseline PAINS-pNF chronic target PN pain intensity score >= 3 | 50 Participants | 53 Participants | 103 Participants |
| BSA | 1.713 m^2 STANDARD_DEVIATION 0.2319 | 1.732 m^2 STANDARD_DEVIATION 0.262 | 1.722 m^2 STANDARD_DEVIATION 0.2471 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 9 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 63 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Geographical region China | 11 count | 13 count | 24 count |
| Geographical region Europe (includes France, Germany, Italy, Poland, Russia, Spain, and United Kingdom) | 31 count | 30 count | 61 count |
| Geographical region Japan | 7 count | 8 count | 15 count |
| Geographical region Rest of World (includes Australia, Brazil, Canada, and United States) | 22 count | 23 count | 45 count |
| Height | 163.517 cm STANDARD_DEVIATION 9.3702 | 165.798 cm STANDARD_DEVIATION 12.2517 | 164.698 cm STANDARD_DEVIATION 10.9784 |
| Race Asian | 22 Participants | 23 Participants | 45 Participants |
| Race Black or African American | 6 Participants | 3 Participants | 9 Participants |
| Race Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race Other | 2 Participants | 3 Participants | 5 Participants |
| Race White | 38 Participants | 43 Participants | 81 Participants |
| Sex: Female, Male Female | 38 Participants | 32 Participants | 70 Participants |
| Sex: Female, Male Male | 33 Participants | 42 Participants | 75 Participants |
| Weight | 65.896 kg STANDARD_DEVIATION 15.9763 | 66.271 kg STANDARD_DEVIATION 17.3971 | 66.087 kg STANDARD_DEVIATION 16.6596 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 74 |
| other Total, other adverse events | 70 / 71 | 54 / 74 |
| serious Total, serious adverse events | 10 / 71 | 9 / 74 |
Outcome results
Primary
Confirmed Partial and Complete Response Rate (ORR) by End of Cycle 16 Using Volumetric MRI Analysis as Determined by ICR (Per REiNS Criteria) in Participants With NF1 Who Have Symptomatic, Inoperable PN.
Objective response rate is defined as the proportion of participants who have a confirmed CR (defined as disappearance of the target PN, confirmed by a consecutive scan within 3 to 6 months after the first response) or confirmed PR (defined as a target PN volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3 to 6 months after the first response) by end of Cycle 16 as determined by ICR per REiNS criteria. Increase in the volume of the target PN by 20% or more compared to baseline or the time of best response after documenting a PR is considered as PD.
Time frame: From first dose up until progression (if it occurs prior to the end of Cycle 16), or the last evaluable assessment up to and including the end of Cycle 16, excluding MRI during prolonged study intervention interruption (defined as interruption >= 28 days)
Population: Full analysis set - All patients who are randomized to study intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 25 mg/m2 | Confirmed Partial and Complete Response Rate (ORR) by End of Cycle 16 Using Volumetric MRI Analysis as Determined by ICR (Per REiNS Criteria) in Participants With NF1 Who Have Symptomatic, Inoperable PN. | 19.7 Percentage |
| Placebo | Confirmed Partial and Complete Response Rate (ORR) by End of Cycle 16 Using Volumetric MRI Analysis as Determined by ICR (Per REiNS Criteria) in Participants With NF1 Who Have Symptomatic, Inoperable PN. | 5.4 Percentage |
p-value: 0.0112Fisher Exact
Secondary
(First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Primary Analysis
The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo in participants with a PAINS-pNF chronic target PN pain score of ≥ 3 at baseline is presented.
Time frame: Baseline and end of cycle 12 of study intervention
Population: Pain full analysis set - subjects randomised to study intervention with a baseline PAINS-pNF chronic target PN pain intensity score \>= 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Selumetinib 25 mg/m2 | (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Primary Analysis | -2.0 Scores on a scale | Standard Error 0.3 |
| Placebo | (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Primary Analysis | -1.3 Scores on a scale | Standard Error 0.29 |
p-value: 0.0795% CI: [-1.6, 0.1]Mixed Models Analysis
Secondary
(First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Supplemental Analysis
The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo participants is presented.
Time frame: Baseline and end of cycle 12 of study intervention
Population: Full analysis set - subjects randomised to study intervention
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Selumetinib 25 mg/m2 | (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Supplemental Analysis | -1.6 Scores on a scale | Standard Error 0.22 |
| Placebo | (First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Supplemental Analysis | -0.9 Scores on a scale | Standard Error 0.21 |
Comparison: supplementary analysis is not controlled for multiplicity.p-value: 0.02495% CI: [-1.3, -0.1]Mixed Models Analysis
Secondary
(Second Key Secondary Endpoint) The Difference of the Means in the Change From Baseline in PlexiQoL Total Score at Cycle 12
PlexiQoL (Plexiform Neurofibroma Quality of Life scale) is a patient-derived QoL measure specific to adults with NF1-associated PNs. It assesses the impact of PNs on patients' ability to fulfil their human needs. The measure consists of 18 dichotomous items with 0 =Not True and 1 = True. PlexiQoL total scores were calculated by the sum of all items to a maximum of 18, with lower scores indicating better quality of life. The change from baseline to the end of each cycle in PlexiQoL total score was derived as the PlexiQoL total score at the cycle 12 minus baseline PlexiQoL total score and presented.
Time frame: Baseline and end of Cycle 12 of study intervention
Population: Full analysis set - subjects randomised to study intervention
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Selumetinib 25 mg/m2 | (Second Key Secondary Endpoint) The Difference of the Means in the Change From Baseline in PlexiQoL Total Score at Cycle 12 | -0.4 Scores on a scale | Standard Error 0.45 |
| Placebo | (Second Key Secondary Endpoint) The Difference of the Means in the Change From Baseline in PlexiQoL Total Score at Cycle 12 | -0.3 Scores on a scale | Standard Error 0.44 |
p-value: 0.91895% CI: [-1.2, 1.1]Mixed Models Analysis