Cachexia, Non-Small Cell Lung Cancer
Conditions
Brief summary
The administration of Anamorelin in patients with Stage III-IV non-small cell lung cancer-cachexia (NSCLC-C) is expected to increase appetite, lean body mass, weight gain, and muscle strength.
Detailed description
This is a randomized, double-blind, placebo-controlled, multicenter study to assess the safety and efficacy of Anamorelin in patients with non-small cell lung cancer-cachexia (NSCLC-C). The primary efficacy analysis will include the treatment difference in the change in lean body mass and physical function. Pharmacokinetic (PK) samples will also be collected at Day 43 visit for population PK.
Interventions
DRUGAnamorelin HCl
Anamorelin HCl will be orally administered daily at least one hour before meal
DRUGPlacebo
Placebo tablets identical in appearance to active tablets; oral administration QD for 12 weeks, at least 1 hour before meal
Sponsors
Helsinn Therapeutics (U.S.), Inc
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
* Documented diagnosis of unresectable Stage III or Stage IV NSCLC * Patients may be receiving maintenance chemotherapy * Patients planning to initiate a new chemotherapy and/or radiation therapy regimen may do so only within ± 14 days of randomization * Patients may have completed a chemotherapy and/or radiation therapy and/or have no plan to initiate a new regimen within 12 weeks from randomization; at least 14 days must elapse from the completion of the chemotherapy and/or radiation therapy prior to randomization * Involuntary weight loss of ≥5% body weight within 6 months prior to screening or a screening body mass index (BMI) \<20 kg/m2 * Body mass index ≤30 kg/m2 * Life expectancy of \>4 months at time of screening * ECOG performance status ≤2 * Adequate hepatic function, defined as AST and ALT levels ≤5 x upper limit of normal * Adequate renal function, defined as creatinine ≤2 x upper limit of normal, or calculated creatinine clearance \>30 ml/minute * Ability to understand and comply with the procedures for the HGS evaluation * If a woman of childbearing potential or a fertile man, he/she must agree to use an effective form of contraception during the study and for 30 days following the last dose of study drug (an effective form of contraception is abstinence, a hormonal contraceptive, or a double-barrier method) * Must be willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures
Exclusion criteria
* Other forms of lung cancer (e.g., small cell, mesothelioma) * Women who are pregnant or breast-feeding * Known HIV, hepatitis (B&C), or active tuberculosis * Had major surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization; patients must be well recovered from acute effects of surgery prior to screening; patients should not have plans to undergo major surgical procedures during the treatment period * Currently taking prescription medications intended to increase appetite or treat weight loss; these include, but are not limited to, testosterone, androgenic compounds, megestrol acetate, methylphenidate, and dronabinol * Inability to readily swallow oral tablets; patients with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption, or obstructive symptoms) or intractable or frequent vomiting are excluded * Has an active, uncontrolled infection * Has uncontrolled diabetes mellitus * Has untreated clinically relevant hypothyroidism * Has known or symptomatic brain metastases * Receiving strong CYP3A4 inhibitors within 14 days of randomization * Receiving tube feedings or parenteral nutrition (either total or partial); patients must have discontinued these treatments for at least 6 weeks prior to Day 1, and throughout the study duration * Other clinical diagnosis, ongoing or intercurrent illness that in the Investigator's opinion would prevent the patient's participation * Has had previous exposure to Anamorelin HCl * Patients actively receiving a concurrent investigational agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lean Body Mass | Change in Lean Body Mass from Baseline Over 12 Weeks | Change in Lean Body Mass (LBM) from baseline over 12 weeks for the ITT Population. Change from baseline over 12 weeks was defined as the average of the change from baseline at Week 6 and the change from baseline at Week 12. |
| Change in Handgrip Strength | Change in Handgrip Strength of the Non-Dominant Hand from Baseline Over 12 Weeks | Change in Handgrip Strength (HGS) of the non-dominant hand from baseline over 12 weeks for the ITT Population. Change from baseline over 12 weeks was defined as the average of the change from baseline at Week 6 and the change from baseline at Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in A/CS Domain Score | Change in FAACT A/CS Domain Score from Baseline Over 12 Weeks | The Functional Assessment of Anorexia/Cachexia Treatment (FAACT) Additional Concerns Subscale (A/CS domain) is a 12-item scale that is part of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System. Each item is answered on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). The 12-items are summed together to obtain the domain score. Note that negatively phrased questions are reverse scored so that higher scores always represent improvement/less symptom burden. The total possible score for the A/CS domain ranges from 0 (worst) to 48 (best). |
| Change in FACIT-F Fatigue Domain Score | Change in FACIT-F Fatigue Domain Score from Baseline Over 12 Weeks | The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) fatigue domain is a 13-item scale that is part of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System. Each item is answered on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). The 13-items are summed together to obtain the domain score. Note that negatively phrased questions are reverse scored so that higher scores always represent improvement/less symptom burden. The total possible score for the FACIT-F fatigue domain ranges from 0 (worst) to 52 (best). |
| Change in Body Weight | Change in Body Weight from Baseline Over 12 Weeks | Change in body weight (BW) from baseline overall (i.e., over 12 weeks) for the MITT Population. |
Countries
Belarus, Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Netherlands, Poland, Russia, Serbia, Slovenia, Spain, Ukraine, United States
Participant flow
Recruitment details
Approximately 477 patients with advanced NSCLC-C (defined as unresectable Stage III and Stage IV and a weight loss of ≥ 5% body weight within 6 months prior to screening or a screening body mass index \[BMI\] \< 20 kg/m2) were to be randomized 2:1 to anamorelin HCl 100 mg or placebo.
Pre-assignment details
Central randomization stratified patients by geographic region, by chemotherapy and/or radiation therapy status and by weight loss over prior 6 months.
Participants by arm
| Arm | Count |
|---|---|
| Anamorelin HCl Active drug; 100 mg tablets; oral administration QD for 12 weeks, at least 1 hour before the first meal of the day. | 323 |
| Placebo Placebo tablets identical in appearance to active tablets; oral administration QD for 12 weeks, at least 1 hour before the first meal of the day. | 161 |
| Total | 484 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 38 | 20 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 8 | 7 |
| Overall Study | Study drug-related AE | 1 | 0 |
| Overall Study | Unrelated AE | 12 | 3 |
| Overall Study | Withdrawal by patient | 32 | 10 |
Baseline characteristics
| Characteristic | Anamorelin HCl | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 108 Participants | 56 Participants | 164 Participants |
| Age, Categorical Between 18 and 65 years | 215 Participants | 105 Participants | 320 Participants |
| Geographic region Australia | 0 Participants | 0 Participants | 0 Participants |
| Geographic region East Europe + Russia | 166 Participants | 82 Participants | 248 Participants |
| Geographic region North America | 35 Participants | 17 Participants | 52 Participants |
| Geographic region West Europe | 122 Participants | 62 Participants | 184 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 319 Participants | 159 Participants | 478 Participants |
| Region of Enrollment Belarus | 15 participants | 9 participants | 24 participants |
| Region of Enrollment Belgium | 11 participants | 4 participants | 15 participants |
| Region of Enrollment Canada | 9 participants | 6 participants | 15 participants |
| Region of Enrollment Czech Republic | 16 participants | 11 participants | 27 participants |
| Region of Enrollment France | 8 participants | 6 participants | 14 participants |
| Region of Enrollment Germany | 10 participants | 3 participants | 13 participants |
| Region of Enrollment Italy | 9 participants | 5 participants | 14 participants |
| Region of Enrollment Netherlands | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 48 participants | 26 participants | 74 participants |
| Region of Enrollment Russian Federation | 8 participants | 4 participants | 12 participants |
| Region of Enrollment Serbia | 10 participants | 3 participants | 13 participants |
| Region of Enrollment Slovenia | 5 participants | 4 participants | 9 participants |
| Region of Enrollment Spain | 13 participants | 3 participants | 16 participants |
| Region of Enrollment Ukraine | 133 participants | 66 participants | 199 participants |
| Region of Enrollment United States | 26 participants | 11 participants | 37 participants |
| Sex: Female, Male Female | 76 Participants | 40 Participants | 116 Participants |
| Sex: Female, Male Male | 247 Participants | 121 Participants | 368 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 182 / 320 | 84 / 161 |
| serious Total, serious adverse events | 82 / 320 | 48 / 161 |
Outcome results
Primary
Change in Handgrip Strength
Change in Handgrip Strength (HGS) of the non-dominant hand from baseline over 12 weeks for the ITT Population. Change from baseline over 12 weeks was defined as the average of the change from baseline at Week 6 and the change from baseline at Week 12.
Time frame: Change in Handgrip Strength of the Non-Dominant Hand from Baseline Over 12 Weeks
Population: Intent-to-Treat Population. Some patients in the ITT population were excluded from the primary LBM/HGS analysis (i.e., multiple imputations/ranking method) if they survived to Week 12 but missed their baseline covariates including LBM, HGS, or ECOG OR had Week 6 and Week 12 outcomes that were outside the visit windows.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anamorelin HCl | Change in Handgrip Strength | -1.10 kg |
| Placebo | Change in Handgrip Strength | -1.58 kg |
Comparison: Superiority analysisp-value: 0.1475Wilcoxon rank sum test
Primary
Change in Lean Body Mass
Change in Lean Body Mass (LBM) from baseline over 12 weeks for the ITT Population. Change from baseline over 12 weeks was defined as the average of the change from baseline at Week 6 and the change from baseline at Week 12.
Time frame: Change in Lean Body Mass from Baseline Over 12 Weeks
Population: Intent-to-Treat Population. Some patients in the ITT population were excluded from the primary LBM/HGS analysis (i.e., multiple imputations/ranking method) if they survived to Week 12 but missed their baseline covariates including LBM, HGS, or ECOG OR had Week 6 and Week 12 outcomes that were outside the visit windows.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anamorelin HCl | Change in Lean Body Mass | 0.99 kg |
| Placebo | Change in Lean Body Mass | -0.47 kg |
Comparison: Superiority analysisp-value: <0.0001Wilcoxon rank sum test
Secondary
Change in A/CS Domain Score
The Functional Assessment of Anorexia/Cachexia Treatment (FAACT) Additional Concerns Subscale (A/CS domain) is a 12-item scale that is part of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System. Each item is answered on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). The 12-items are summed together to obtain the domain score. Note that negatively phrased questions are reverse scored so that higher scores always represent improvement/less symptom burden. The total possible score for the A/CS domain ranges from 0 (worst) to 48 (best).
Time frame: Change in FAACT A/CS Domain Score from Baseline Over 12 Weeks
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Anamorelin HCl | Change in A/CS Domain Score | 4.12 scores on a scale | Standard Error 0.752 |
| Placebo | Change in A/CS Domain Score | 1.92 scores on a scale | Standard Error 0.805 |
Comparison: Superiority analysisp-value: 0.0004Mixed Models Analysis
Secondary
Change in Body Weight
Change in body weight (BW) from baseline overall (i.e., over 12 weeks) for the MITT Population.
Time frame: Change in Body Weight from Baseline Over 12 Weeks
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Anamorelin HCl | Change in Body Weight | 2.20 kg | Standard Error 0.326 |
| Placebo | Change in Body Weight | 0.14 kg | Standard Error 0.363 |
Comparison: Superiority analysisp-value: <0.0001Mixed Models Analysis
Secondary
Change in FACIT-F Fatigue Domain Score
The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) fatigue domain is a 13-item scale that is part of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System. Each item is answered on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). The 13-items are summed together to obtain the domain score. Note that negatively phrased questions are reverse scored so that higher scores always represent improvement/less symptom burden. The total possible score for the FACIT-F fatigue domain ranges from 0 (worst) to 52 (best).
Time frame: Change in FACIT-F Fatigue Domain Score from Baseline Over 12 Weeks
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Anamorelin HCl | Change in FACIT-F Fatigue Domain Score | 0.26 scores on a scale | Standard Error 0.886 |
| Placebo | Change in FACIT-F Fatigue Domain Score | -1.19 scores on a scale | Standard Error 0.933 |
Comparison: Superiority analysisp-value: 0.0544Mixed Models Analysis