| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer anorexia and weight loss |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack or loss of appetite and weight loss associated with cancer. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002646 |
| E.1.2 | Term | Anorexia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Stage 1 (Phase 1) -Primary Objectives
• Determine the safety profile of ART27.13 in patients with cancer anorexia at different doses.
• Determine dose-limiting toxicity, if any, within the range of doses used during the 4 weeks after the first dose of ART27.13.
• Determine the most effective, safe dose (recommended Phase 2 dose, or RP2D) to be as a starting dose in Stage 2.
Stage 2 (Phase 2): Primary Objectives
• Determine point estimates of activity of ART27.13 in terms of weight gain, lean body mass, KPS, and improvement of anorexia at the Stage 2 doses at 4, 8, and 12 weeks with intra-patient dose escalation at 4-week intervals. Those patients who are enrolled prior to the design changes being implemented will be dosed at a stable dose of 650μg for the entire 12 week duration. |
|
| E.2.2 | Secondary objectives of the trial |
Stage 1 (phase 1): Secondary Objectives
• Assess the activity of ART27.13 in the patient population in terms of increase in lean body mass, weight gain, and improvement of anorexia.
• Assess quality of life (QoL) of patients.
• Determine the pharmacokinetic profile of ART27.13 in the patient population.
• Assess any change in Karnofsky Performance Status (KPS)
Stage 2 (Phase 2): Secondary Objectives
• Continue to assess the safety profile of ART27.13 in patients with cancer anorexia.
• Assess QoL of patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have cancer (except those excluded by the exclusion criteria) documented by histopathology or cytology.
2. Have anorexia as determined by self-reported decrease or lack of appetite or aversion to food.
3. Have documented, unintentional weight loss of >5% of body weight and a continuous downward trend of weight loss in the past 6 months (± 2 weeks) dating back from the date of enrollment.
4. Patients are on either:
4.1 no anti-cancer therapy for the 2 weeks before enrollment and are not expected to have anti-cancer therapy for the first 12 weeks after the first dose of ART27.13 (Stage 1) or if in Stage 2, after the start of ART27.13/placebo; or
4.2 stable dosing from 2 weeks before enrollment and expected to be on such therapy for another 12 weeks of anti-cancer therapy as described in Appendix 17 in the protocol.
5. Estimated life expectancy of at least 12 weeks as judged by the Investigator based on clinical impression.
6. Have a KPS of >50.
7. At least 18 years of age at the time of enrollment.
8. Adequate hematological, renal, and hepatic function based on laboratory values obtained within 14 days of randomization:
• Absolute neutrophil count ≥ 1.0 X 10⁹/L
• Platelets ≥ 75 X 10⁹/L.
• Serum creatinine ≤ 1.5 times ULN.
• Total serum bilirubin ≤ 1.5 times ULN ( ≤ 3.0 times ULN if patient has been diagnosed with Gilbert’s syndrome)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (AP) ≤ 2.5 times ULN
9. For women of child-bearing potential and for men with partners of child-bearing potential, patient must agree to take contraceptive measures for duration of treatments and for 6 months after last study treatment.
10. Understand and voluntarily sign and date an Informed Consent Document prior to any study related assessments/procedures.
11. Willing and able to adhere to the study visit schedule and other protocol requirements.
12a. Agree to not driving or operating heavy machinery for the first 4 weeks of treatment or longer if AEs warrant as known AEs of ART27.13 include dizziness and somnolence. |
|
| E.4 | Principal exclusion criteria |
1. Primary brain tumors or symptomatic brain metastases.
2. Unable to swallow food or medication capsules.
3. Patients with oral mucositis or oral fungal infection causing anorexia or impairing taste.
4. Have a disorder that causes obstruction of the gastrointestinal tract or limits the absorption of calories such as bowel obstruction or celiac disease.
5. Receiving tube feedings or parenteral nutrition.
6. Be on, been on within 4 weeks prior to enrollment, or expected to be on medications that have the potential to affect anorexia or caloric intake. Examples of such medications include any synthetic or natural cannabinoid (inhaled or administered by any other route) and megestrol.
7. Be on, been on within 4 weeks prior to enrollment, or expected to be on medications that are known to be strong CYP3A4 inhibitors or inducers,
8a. Corticosteroids are allowed if on a stable or tapering dose for 2 weeks prior to enrollment. Patients taking inhaled corticosteroids are permitted.
9a. History of any recreational or illicit drug use, alcohol misuse, or other drug misuse. Current illicit drug use or recreational or medicinal use of cannabinoids is also excluded.
10a. Known hypersensitivity to ART27.13 or any of its excipients. A list of ingredients of ART27.13 capsules will be provided to sites prior to the start of Stage 1 of the protocol. Prior to the start of Stage 2, the list of ingredients will be provided for placebo.
11a. Pregnant or breast feeding.
12a. Clinically significant depression requiring current use of antidepressant medications. Patients who are already stable on antidepressant medication are permitted.
13a. Condition other than cancer that could cause anorexia and/or weight loss such as AIDS, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, or pathological eating disorder.
14a. Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous (IV) antibiotics & psychiatric illness/social situations that would limit compliance with study requirements.
15a. Major surgery within 2 weeks prior to enrollment.
16a. Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor.
17a. Known human immunodeficiency virus infection, acute or chronic hepatitis B, or acute hepatitis C infection.
18a. Clinically significant ascites requiring or expected to require paracentesis.
19a. Corrected QT intervals (QTc) intervals calculated according to Fridericia’s formula (QTcF) >480 ms.
20a. Anticipated need for anti-cancer therapy from 2 weeks prior to enrollment and 12 weeks after the first dose of ART27.13 or in Stage 2 ART27.13/placebo. (Continued use of certain anti-cancer therapy is allowed.)
21a. Investigational agent within 4 weeks prior to enrollment or expected need for an investigational agent for 12 weeks after the first dose of ART27.13 or in Stage 2 placebo.
22a. Receiving radiotherapy within 2 weeks dating back from enrollment or anticipated to need radiotherapy within 12 weeks of enrollment. Short term palliative radiation treatment involving a local lesion is allowed.
23. Patients who have previously participated in a study with ART27.13 would be excluded. Patients who fail screening can be rescreened a maximum of 1 time if the Investigator believes that the reason for screen failure may resolve. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1 Primary Endpoints (Safety):
1. Analysis of the type of, frequency, and severity of adverse drug effects as determined by AEs and the evaluation of routine chemistry and hematologic values, urinalyses, vital signs, and electrocardiograms.
2. Assessment of type and incidence of dose-limiting toxicity (DLT).
3. Most effective, safe starting dose to be used in Stage 2. Effectiveness is based primarily on the endpoint of lean body mass and weight gain after the first cycle.
Stage 2 Primary Endpoints (Activity):
• Change in lean body mass as determined by weight and DEXA scans at 4, 8, and 12 weeks.
• Change in anorexia as determined by a visual analog scale (VAS) and (FAACT) questionnaire.
• Change in KPS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1 Primary Endpoints (Safety):
1. AEs: Duration of trial. Chemistry, Hematology, Vital signs: Days pre-dose, 8, 15, 22, 29, 43, 57, 71, EOT, FU. Urinalyses: Days 29, 57, EOT, FU. ECG: Days pre-dose, 8, 15, 22, 29, 43, 57, EOT, FU. [All +/-3 Days except for EOT]
2. DLTs: Reported throughout duration of study.
3. Safe start dose for Stage 2: Lean body mass and weight gain at 4 weeks.
Stage 2 Primary Endpoints (Activity):
1. DEXA scans: at 4, 8 and 12 weeks.
2. VAS: Days pre-dose, 29, 57, EOT, FU. FAACT questionnaire: Days pre-dose, 15, 29, 57, EOT, FU [All +/-3 Days except for EOT]
3. KPS: Days pre-dose, 8, 15, 22, 29, 57, EOT, FU [All +/-3 Days except for EOT] |
|
| E.5.2 | Secondary end point(s) |
Stage 1 Secondary Endpoints (Activity):
1. Change in lean body mass as determined by weight and DEXA scans.
2. Change in anorexia as determined by a visual analog scale (VAS).
3. Assess QoL using the Functional Assessment of Anorexia Cachexia Therapy (FAACT), the patient-generated subjective global assessment (PG-SGA), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL, and revised Edmonton Symptom Assessment Scale (ESAS-r) questionnaires.
4. Change in KPS.
Stage 2 Secondary Endpoints (Activity):
(Safety):
1. Assessment of the safety profile of ART27.13 by analyzing the type of, frequency, and severity of adverse drug effects as determined by reporting AEs and evaluation of routine chemistry and hematologic values, urinalyses, vital signs, and electrocardiograms.
(Quality of Life):
2. Assess QoL using the Functional Assessment of Anorexia Cachexia Therapy (FAACT), the patient-generated subjective global assessment (PG-SGA), the EORTC QLQ-C15-PAL, and revised Edmonton Symptom Assessment Scale (ESAS-r) questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1 Secondary Endpoints (Activity):
1. Weight: Days pre-dose, 8, 15, 22, 29, 43, 57, 71, EOT, FU. DEXA scans: Days pre-dose, 29, EOT, FU. [All +/-3 Days except for EOT]
2. VAS: Days pre-dose, 29, 57, EOT, FU.
3. FAACT, and ESAS-r questionnaires: Days pre-dose, 15, 29, 57, EOT, FU. The PG-SGA and EORTC QLQ-C15-PAL: Days pre-dose, 15, 22, EOT, FU. [All +/-3 Days except for EOT]
Stage 2 Secondary Endpoints:
1. AEs: Duration of trial. Chemistry, Hematology, Vital signs: Days pre-dose, 8, 15, 22, 29, 43, 57, 71, EOT, FU. Urinalyses: Days 29, 57, EOT, FU. ECG: Days pre-dose, 8, 15, 22, 29, 43, 57, EOT, FU.
2. FAACT, and ESAS-r questionnaires: Days pre-dose, 15, 29, 57, EOT, FU. PG-SGA, EORTC QLQ-C15-PAL questionnaires: Days pre-dose, 15, 29, EOT, FU. [All +/-3 Days except for EOT] |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 1/2 performed in 2 stages: Stage 1 is an ascending dose trial. Stage 2 is a RCT. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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