Cachexia; Cancer, Non Small Cell Lung Cancer
Conditions
Brief summary
The goal of this clinical trial was to compare the efficacy and safety of anamorelin HCl (the investigational drug) to that of placebo (tablet with no drug) in patients with advanced non-small cell lung cancer and cachexia (cancer-related weight loss). The main question it aimed to answer was as follows: Do patients who receive anamorelin HCl gain more body weight and show more improvement in anorexia symptoms than those who receive placebo. Approximately 316 patients were to be enrolled in the study. Of these patients, an equal number were to be assigned to each treatment group (anamorelin HCl or placebo). Participants were to take their assigned study drug by mouth once daily for a total of 24 weeks. During this treatment period, the patients were to visit the clinical study site every 3 weeks for health and other study-related assessments. Two weeks after the last treatment, patients were to receive a follow-up phone call.
Detailed description
The study was a multicenter, randomized, double-blind, parallel-group, placebo controlled study to evaluate the efficacy and safety of anamorelin HCl. It was planned that approximately 316 patients with advanced NSCLC with cachexia were to be randomized 1:1 to anamorelin HCl 100 mg or placebo (158 patients per treatment group). The study treatment was to be taken orally once daily for a total of 24 weeks. Patients were instructed to take the study drug at least 1 hour before their first meal of the day. Central randomization was stratified by line of systemic anti-cancer treatment (first line vs second line vs third line or higher), by type of anti-cancer therapy (immunotherapy vs non-immunotherapy), and by baseline score of the 5-item Anorexia Symptom Subscale (5-IASS) (≤10 vs \>10). Patients who had never received anti-cancer treatment prior to entering the study but who met all eligibility criteria were eligible to enter the study and were assigned to receive first line treatment in the Interactive Web Response System (IWRS). Patients were to visit the site every 3 weeks for the study Treatment Period of 24 weeks. A follow-up telephone visit was to be scheduled at Week 26. Thus, patients were enrolled in the study for a maximum duration of 27 weeks (including a 1-week Screening Period, a 24-week Treatment Period, and a 2-week Follow-up Period). Each patient was scheduled to have a total of 10 planned visits plus 1 telephone contact for the Follow-up Visit.
Interventions
100 mg anamorelin HCl (administered as 100 mg tablets in the fasted condition)
DRUGPlacebo Oral Tablet
Placebo (administered as matching placebo tablets in the fasted condition)
Sponsors
Helsinn Healthcare SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This was a double-blind study. The blinding of the study drugs was guaranteed by the use of anamorelin HCl film-coated tablets and matching placebo tablets. Patients were randomized using the Interactive Web Response System (IWRS). Any unblinding of the study treatment was performed using the IWRS.
Intervention model description
Randomized, Double-Blind, Placebo-Controlled, Multicenter Study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent 2. Female or male ≥18 years of age 3. Documented histologic or cytologic diagnosis of American Joint Committee on Cancer (AJCC) Stage III or IV NSCLC. Stage III patient must have unresectable disease 4. Body mass index \< 20 kg/m2 with involuntary weight loss of \>2% within 6 months prior to screening 5. Ongoing problems with appetite/eating associated with the underlying cancer, as determined by having score of ≤ 17 points on the 5-item Anorexia Symptom Scale and ≤ 37 points on the 12-item FAACT A/CS 6. Patient receiving or not receiving systemic anti-cancer treatment at the time of screening are eligible to participate. Systemic anti-cancer treatment includes first, second, third treatment line with chemotherapy/radiation therapy, immunotherapy or targeted therapy. Patient not receiving systemic anti-cancer treatment is eligible if: 1. Not planning to receive anti-cancer treatment and/or at least 14 days must be elapsed from the completion of prior treatment at the day of screening, in case underwent previous cycle OR 2. Planning to receive anti-cancer treatment within 14 days from randomization and/or at least 14 days must be elapsed from the completion of prior treatment at the day of screening, in case underwent previous cycle OR 3. Patient on palliative care treatment 7. ECOG performance status 0,1 or 2 at screening 8. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN or if hepatic metastases are present ≤ 5 x ULN 9. Adequate renal function, defined as creatinine ≤2 ULN, or calculated creatinine clearance \>30 ml/minute 10. Female patient shall be: a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to first dose of investigational product. Notes: 1. Female patient of non-childbearing potential are defined as being in post-menopausal state since at least 1 year; or having documented surgical sterilization or hysterectomy at least 3 months before study participation. 2. Reliable contraceptive measures include implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized partner or complete (long term) sexual abstinence. 11. The patient must be willing and able to comply with the protocol tests and procedures. All inclusion criteria were to be checked at screening visit (Visit 1). Inclusion criterion #10 was to be re-checked and verified at Day 1 (Visit 2).
Exclusion criteria
1. Patient with other forms of lung cancer (e.g., small cell, neuroendocrine tumors) 2. Woman who is pregnant or breast-feeding 3. Reversible causes of reduced food intake, as determined by the Investigator. These causes may include but are not limited to: 1. NCI CTCAE Grade 3 or 4 oral mucositis, 2. NCI CTCAE Grade 3 or 4 GI disorders \[nausea, vomiting, diarrhea, and constipation\], 3. mechanical obstructions making patient unable to eat, or 4. severe depression 4. Patient undergoing major surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization. Patient must be well recovered from acute effects of surgery prior to screening. Patient should not have plans to undergo major surgical procedures during the treatment period. 5. Patient currently taking androgenic compounds including but not limited to testosterone, testosterone-like agents, oxandrolone; megestrol acetate; corticosteroids; olanzapine, mirtazapine (however, long-term use of mirtazapine for depression for at least four weeks prior to screening is allowed); dronabinol; marijuana (cannabis); or any other prescription medication or off-label products intended to increase appetite or treat unintentional weight loss 6. Patient with pleural effusion requiring thoracentesis, pericardial effusion requiring drainage, edema or evidence of ascites 7. Patient with uncontrolled or significant cardiovascular disease, including: 1. History of myocardial infarction within the past 3 months 2. A-V block of second or third degree (may be eligible if currently have a pacemaker) 3. Unstable angina 4. Congestive heart failure within the past 3 months, if defined as NYHA class III-IV 5. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW) syndrome, or torsade de pointes) 6. Uncontrolled hypertension (blood pressure \>150 mm Hg systolic and \>95 mm Hg diastolic) 7. Heart rate \< 50 beats per minute on pre-entry electrocardiogram and patient is symptomatic 8. Patient on drugs that may prolong the PR or QRS interval durations, such as any of the antiarrhythmic medications Class I (Fast sodium (Na) channel blockers) 9. Patient unable to readily swallow oral tablets 10. Patient with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption) 11. Patient with history of gastrectomy 12. Patient with uncontrolled diabetes mellitus or unmonitored diabetes mellitus 13. Patient with cachexia caused by other reasons, as determined by the investigator such as: 1. Severe COPD requiring use of home O2, 2. New York Heart Association (NYHA) class III-IV heart failure 3. AIDS 4. Uncontrolled thyroid disease 14. Patient receiving strong CYP3A4 inhibitors within 14 days of randomization 15. Patient currently receiving tube feedings or parenteral nutrition (either total or partial). 16. Current excessive alcohol or illicit drug use 17. Any condition, including the presence of laboratory abnormalities, which in the Investigator's opinion, places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study 18. Enrollment in a previous study with anamorelin HCl 19. Patient actively receiving a concurrent investigational agent, or having received an investigational agent within 28 days of Day 1 All
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Body Weight Over 12 Weeks | Mean change from baseline over 12 weeks. | This co-primary efficacy endpoint was mean change from baseline in body weight (kg) over 12 weeks in the anamorelin HCl group versus placebo group. Mean change was computed as sum of the changes from baseline over 12 weeks by the time of the last assessment (either week 12 or before in case of death), and then divided by the number of assessments (observed or imputed) from baseline up to the time of the last assessment. |
| Mean Change From Baseline in 5-item Anorexia Symptom Subscale (5-IASS) Over 12 Weeks | Mean change from baseline over 12 weeks. | This co-primary efficacy endpoint was mean change from baseline in 5-IASS (points) over 12 weeks in the anamorelin HCl group versus placebo group. Mean change was computed as sum of the changes from baseline over 12 weeks by the time of the last assessment (either week 12 or before in case of death), and then divided by the number of assessments (observed or imputed) from baseline up to the time of the last assessment. FAACT-A/CS (Functional Assessment Anorexia Cachexia Therapy) is a 12-item measure of patients' perceptions of anorexia/cachexia symptoms and concerns. From this questionnaire, the 5-item section referring to anorexia symptoms (i.e., good appetite, interest in food drops, food tastes unpleasant, get full quickly, and difficulty eating rich/heavy foods) was used to assess 5-IASS. The range of possible scores is 0-20. Higher scores indicate lower levels of symptom burden. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥0 kg) | Duration of treatment benefit from baseline over 12 weeks. | The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in body weight of ≥0 kg. |
| Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥1.5 kg) | Duration of treatment benefit from baseline over 12 weeks. | The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in body weight of ≥1.5 kg. |
| Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥0 Points) | Duration of treatment benefit from baseline over 12 weeks. | The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in 5-IASS of ≥0 points. |
| Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥3 Points) | Duration of treatment benefit from baseline over 12 weeks. | The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in 5-IASS of ≥3 points. |
Countries
Bulgaria, Hungary, Italy, Romania, Russia, Serbia, United States
Participant flow
Recruitment details
Patients were enrolled at a total of 46 study sites in Bulgaria (4 sites), Hungary (5 sites), Italy (5 sites), Romania (6 sites), Russia (10 sites), Serbia (5 sites), and USA (11 sites). First Patient Enrollment (date of randomization) was on 05MAR2019.
Pre-assignment details
The protocol had pre-defined criteria regarding health and medication requirements to begin study drug administration, and if the patient's status for these requirements changed between screening and Study Day 1, treatment could not be initiated.
Participants by arm
| Arm | Count |
|---|---|
| 100 mg Anamorelin HCl 100 mg anamorelin HCl (administered as film-coated tablets in fasted condition) was to be taken orally once daily for a total of 24 weeks | 159 |
| Placebo Placebo (administered as matching placebo tablets in fasted condition) was to be taken orally once daily for a total of 24 weeks | 159 |
| Total | 318 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 9 |
| Overall Study | Death | 27 | 26 |
| Overall Study | Lost to Follow-up | 4 | 8 |
| Overall Study | Physician Decision | 10 | 15 |
| Overall Study | Reported as Other in Clinical Study Report | 3 | 6 |
| Overall Study | Withdrawal by Subject | 32 | 19 |
Baseline characteristics
| Characteristic | Total | Placebo | 100 mg Anamorelin HCl |
|---|---|---|---|
| 5-IASS Score ≤10 | 217 Participants | 109 Participants | 108 Participants |
| 5-IASS Score >10 | 101 Participants | 50 Participants | 51 Participants |
| Age, Continuous | 63.4 years STANDARD_DEVIATION 9.95 | 62.2 years STANDARD_DEVIATION 10.55 | 64.5 years STANDARD_DEVIATION 9.2 |
| Anti-cancer Treatment Immunotherapy | 95 Participants | 48 Participants | 47 Participants |
| Anti-cancer Treatment Non-immunotherapy | 223 Participants | 111 Participants | 112 Participants |
| Body Mass Index | 18.30 kg/m^2 STANDARD_DEVIATION 1.484 | 18.24 kg/m^2 STANDARD_DEVIATION 1.578 | 18.35 kg/m^2 STANDARD_DEVIATION 1.386 |
| Body weight change within 6 months prior to screening | -11.54 percent change STANDARD_DEVIATION 6.84 | -11.05 percent change STANDARD_DEVIATION 6.489 | -12.04 percent change STANDARD_DEVIATION 7.16 |
| Chemotherapy Line First line | 225 Participants | 113 Participants | 112 Participants |
| Chemotherapy Line Second line | 60 Participants | 31 Participants | 29 Participants |
| Chemotherapy Line Third line | 33 Participants | 15 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 11 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 295 Participants | 148 Participants | 147 Participants |
| Height | 171.28 cm STANDARD_DEVIATION 10.194 | 172.09 cm STANDARD_DEVIATION 9.91 | 170.47 cm STANDARD_DEVIATION 10.438 |
| NSCLC stage at study entry Missing | 10 Participants | 5 Participants | 5 Participants |
| NSCLC stage at study entry Stage IIIA | 4 Participants | 3 Participants | 1 Participants |
| NSCLC stage at study entry Stage IIIB | 55 Participants | 30 Participants | 25 Participants |
| NSCLC stage at study entry Stage IV | 249 Participants | 121 Participants | 128 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 306 Participants | 152 Participants | 154 Participants |
| Region of Enrollment Bulgaria | 93 participants | 43 participants | 50 participants |
| Region of Enrollment Hungary | 42 participants | 23 participants | 19 participants |
| Region of Enrollment Italy | 19 participants | 9 participants | 10 participants |
| Region of Enrollment Romania | 34 participants | 18 participants | 16 participants |
| Region of Enrollment Russia | 56 participants | 27 participants | 29 participants |
| Region of Enrollment Serbia | 51 participants | 28 participants | 23 participants |
| Region of Enrollment United States | 23 participants | 11 participants | 12 participants |
| Sex: Female, Male Female | 90 Participants | 47 Participants | 43 Participants |
| Sex: Female, Male Male | 228 Participants | 112 Participants | 116 Participants |
| Weight | 54.10 kg STANDARD_DEVIATION 8.339 | 54.49 kg STANDARD_DEVIATION 8.627 | 53.71 kg STANDARD_DEVIATION 8.049 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 159 | 26 / 159 |
| other Total, other adverse events | 82 / 159 | 87 / 159 |
| serious Total, serious adverse events | 43 / 159 | 39 / 159 |
Outcome results
Primary
Mean Change From Baseline in 5-item Anorexia Symptom Subscale (5-IASS) Over 12 Weeks
This co-primary efficacy endpoint was mean change from baseline in 5-IASS (points) over 12 weeks in the anamorelin HCl group versus placebo group. Mean change was computed as sum of the changes from baseline over 12 weeks by the time of the last assessment (either week 12 or before in case of death), and then divided by the number of assessments (observed or imputed) from baseline up to the time of the last assessment. FAACT-A/CS (Functional Assessment Anorexia Cachexia Therapy) is a 12-item measure of patients' perceptions of anorexia/cachexia symptoms and concerns. From this questionnaire, the 5-item section referring to anorexia symptoms (i.e., good appetite, interest in food drops, food tastes unpleasant, get full quickly, and difficulty eating rich/heavy foods) was used to assess 5-IASS. The range of possible scores is 0-20. Higher scores indicate lower levels of symptom burden.
Time frame: Mean change from baseline over 12 weeks.
Population: The ITT Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Mean Change From Baseline in 5-item Anorexia Symptom Subscale (5-IASS) Over 12 Weeks | 3.816 score on a scale | Standard Error 0.383 |
| Placebo | Mean Change From Baseline in 5-item Anorexia Symptom Subscale (5-IASS) Over 12 Weeks | 3.194 score on a scale | Standard Error 0.385 |
Comparison: To declare anamorelin superior to the placebo, both co-primary endpoints had to be significant.~The null hypothesis for mean change from baseline over 12 weeks in patient 5-IASS (H0A) and the corresponding alternative (H1A) were:~H0A: MAa = MAp; H1A: MAa ≠ MAp~Where MAa is the mean change from baseline over 12 weeks in 5-IASS for the anamorelin arm and MAp is the mean change from baseline over 12 weeks in 5-IASS for the placebo arm.p-value: 0.151495% CI: [-0.228, 1.472]ANOVA
Primary
Mean Change From Baseline in Body Weight Over 12 Weeks
This co-primary efficacy endpoint was mean change from baseline in body weight (kg) over 12 weeks in the anamorelin HCl group versus placebo group. Mean change was computed as sum of the changes from baseline over 12 weeks by the time of the last assessment (either week 12 or before in case of death), and then divided by the number of assessments (observed or imputed) from baseline up to the time of the last assessment.
Time frame: Mean change from baseline over 12 weeks.
Population: The Intent-to-Treat (ITT) Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Mean Change From Baseline in Body Weight Over 12 Weeks | 1.938 Change from baseline in body weight (kg) | Standard Error 0.285 |
| Placebo | Mean Change From Baseline in Body Weight Over 12 Weeks | 0.594 Change from baseline in body weight (kg) | Standard Error 0.285 |
Comparison: To declare anamorelin superior to placebo, both co-primary endpoints had to be significant.~The null hypothesis for mean change in body weight from baseline over 12 weeks (H0w) and the corresponding alternative hypothesis (H1w) were:~H0w: MWa = MW; H1w: MWa ≠ MWp~Where MWa is the mean change in body weight from baseline over 12 weeks for the anamorelin arm and MWp is the mean change in body weight from baseline over 12 weeks for the placebo arm.p-value: <0.000195% CI: [0.718, 1.971]ANOVA
Secondary
Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥0 Points)
The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in 5-IASS of ≥0 points.
Time frame: Duration of treatment benefit from baseline over 12 weeks.
Population: The ITT Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥0 Points) | 10.523 Weeks | Standard Error 0.362 |
| Placebo | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥0 Points) | 9.496 Weeks | Standard Error 0.359 |
p-value: 0.010895% CI: [0.238, 1.816]ANOVA
Secondary
Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥3 Points)
The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in 5-IASS of ≥3 points.
Time frame: Duration of treatment benefit from baseline over 12 weeks.
Population: The ITT Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥3 Points) | 6.185 Weeks | Standard Error 0.423 |
| Placebo | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in 5-IASS (≥3 Points) | 5.650 Weeks | Standard Error 0.426 |
p-value: 0.260595% CI: [-0.397, 1.466]ANOVA
Secondary
Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥0 kg)
The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in body weight of ≥0 kg.
Time frame: Duration of treatment benefit from baseline over 12 weeks.
Population: The ITT Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥0 kg) | 9.871 Weeks | Standard Error 0.476 |
| Placebo | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥0 kg) | 7.462 Weeks | Standard Error 0.475 |
p-value: <0.000195% CI: [1.367, 3.453]ANOVA
Secondary
Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥1.5 kg)
The duration of treatment benefit over 12 weeks was measured as the period, or the sum of the periods, over 12 weeks (or less in case of death), in which the patient observed a change from baseline in body weight of ≥1.5 kg.
Time frame: Duration of treatment benefit from baseline over 12 weeks.
Population: The ITT Set included all randomized patients and was analyzed as per planned treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Anamorelin HCl | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥1.5 kg) | 4.967 Weeks | Standard Error 0.434 |
| Placebo | Duration of Treatment Benefit (Weeks) From Baseline Over 12 Weeks in Body Weight (≥1.5 kg) | 3.631 Weeks | Standard Error 0.429 |
p-value: 0.005795% CI: [0.388, 2.284]ANOVA