Phase 2 Cachexia Clinical Trial to Evaluate the Efficacy and Safety of ASCA101

A Multi-center, Randomized, Phase 2 Clinical Trial to Exploratively Evaluate the Efficacy and Safety of ASCA101 for the Treatment of Cachexia in Patients With Solid Tumor

The goal of this clinical trial is to evaluate the efficacy and safety of ASCA101 for the treatment of Cachexia in solid tumor patients. The main questions it aims to answer are:

Can the efficacy of ASCA101 in improving cachexia be evaluated based on changes in body weight measured by InBody after 12 weeks (3 cycles) of weekly administration, compared to baseline, for each dose group?

Do participants experience adverse events during administration of ASCA101 and/or within 4 weeks after the end of administration?

This clinical trial comprises two parts. [Study 1. Active-Controlled, Open-Label Study] Participants who provide written informed consent will undergo screening procedures. Those who meet all inclusion criteria and none of the exclusion criteria will be eligible for enrollment and will be randomized to receive either ASCA101 (at one of two dose levels: 24.32 or 32.43 mg/kg) or an active control. Participants will receive the investigational product over 3 cycles (12 weeks). Each cycle consists of 28 days. Subjects in the ASCA101 group will receive the investigational drug twice weekly for a total of 8 doses per cycle. Participants in the active control group (megace F suspension) will receive the drug orally once daily.

[Study 2. Placebo-Controlled, Double-Blind Study] Participants who provide written informed consent will undergo screening procedures. Those who meet all inclusion criteria and none of the exclusion criteria will be eligible for enrollment and will be randomized to receive either ASCA101 (at one of two dose levels: 24.32 or 32.43 mg/kg) or placebo. Participants will receive the investigational product over 3 cycles (12 weeks). Each cycle consists of 28 days. Subjects in the ASCA101 group will receive the investigational drug twice weekly for a total of 8 doses per cycle. Participants in the placebo group will receive placebo in the same manner as the ASCA101 group.

Inclusion Criteria:

To be eligible for enrollment, subjects must meet all of the following criteria.

1. Aged 19 years or older with a histologically or cytologically confirmed diagnosis of a solid tumor (primary tumor types: colorectal cancer, ovarian cancer, and lung cancer [lung cancer applicable to Study 1 only]).

2. Must be either surgically sterilized or postmenopausal*. (For female subjects only)

   *Postmenopause is defined as the permanent cessation of ovarian function, evidenced by the absence of menstruation for 12 consecutive months not attributable to other medical causes.

3. Must meet at least one of the following criteria consistent with cachexia diagnosis*:

   ① Unintentional weight loss of >5% over the past 6 months.

   ② BMI <20 kg/m² with unintentional weight loss of >2% over the past 6 months.

   ③ Diagnosis of sarcopenia (skeletal muscle index: <7.26 kg/m² for men, <5.45 kg/m² for women) with unintentional weight loss of >2% over the past 6 months.

   *For subjects requiring confirmation of sarcopenia for cachexia diagnosis, skeletal muscle mass must be assessed using Dual-Energy X-ray Absorptiometry (DEXA).

4. Clinical laboratory results measured within 14 days prior to randomization must meet the following criteria :

   • Absolute Neutrophil Count (ANC) ≥ 1,000/mm³

     • Platelet count ≥ 75,000/mm³

       • Hemoglobin ≥ 8.0 g/dL ④ Serum creatinine ≤ 2 × upper limit of normal (ULN) ⑤ Total bilirubin ≤ 3 × ULN ⑥ AST and ALT ≤ 3 × ULN (≤ 5 × ULN if liver metastasis is present)

         • INR and aPTT ≤ 1.5 × ULN

5. Able to consume food orally.

6. Able to complete questionnaires.

7. Life expectancy of at least 16 weeks, as assessed by the investigator.

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.

9. Male subjects who have not undergone vasectomy must agree to use highly effective contraception from at least 4 weeks prior to study drug administration, throughout the study period, and for 6 months following the last dose.

   Highly effective contraception includes: partner's hormonal contraception, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, or total sexual abstinence.

10. Able and willing to voluntarily provide written informed consent to participate in this clinical trial.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from enrollment.

1. Patients who meet any of the following criteria:

   ① Are scheduled to undergo surgery requiring general anesthesia for the treatment of cancer.

   ② Are scheduled to switch to, or initiate an additional anticancer treatment regimen other than the chemotherapy (including chemoimmunotherapy) or radiotherapy currently being administered.

   ③ Are receiving, or are scheduled to receive, hormonal therapy or immunotherapy.

2. History of hypersensitivity to any component of the investigational product or to drugs of the same class.

3. Currently taking medications for the purpose of appetite stimulation or weight gain.

4. History of surgery within 3 months prior to screening. (Note: Subjects undergoing postoperative chemotherapy are eligible regardless of the time of surgery.)

5. Subjects requiring dietary restrictions.

6. Subjects requiring enteral or parenteral nutrition.

7. Weight loss due to causes other than malignancy, including:

   • Major endocrine/metabolic disorders (e.g., hyperthyroidism, uncontrolled diabetes mellitus)
   • Conditions affecting appetite or calorie intake (e.g., mechanical bowel obstruction, cholestasis, uncontrolled nausea/vomiting, malabsorption syndromes, severe diarrhea)

8. Conditions that may lead to weight gain, including major endocrine/metabolic diseases (e.g., hypothyroidism, Cushing's syndrome).

9. History of any of the following cardiovascular conditions within the past 5 years:

   • Congestive heart failure (CHF) classified as NYHA Class II or higher, or LVEF

     • 50%

   • Uncontrolled hypertension

   • History of hypertensive crisis or hypertensive encephalopathy

   • Pulmonary hypertension

   • Myocardial infarction

   • Clinically significant vascular disease within 6 months prior to the first dose (e.g., aneurysm requiring surgery, recent peripheral arterial thrombosis)

   • Uncontrolled arrhythmias

10. Persistent clinically significant toxicity (Grade ≥2 per NCI-CTCAE v5.0) due to previous cancer treatment.

11. Subjects with severe infections or severe traumatic systemic conditions.

12. Symptomatic or uncontrolled central nervous system (CNS) metastases. (Note: Subjects with asymptomatic CNS metastases who have discontinued systemic corticosteroids at least 4 weeks prior to randomization and have been radiologically and neurologically stable for ≥4 weeks are eligible.)

13. Patients with one or more contraindications to ascorbic acid injection and/or calcium injection, including:

    • Hyperoxaluria, thalassemia
    • Gout, cystinuria
    • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
    • Calcium oxalate nephrolithiasis
    • Receiving cardiac glycosides
    • Hypercalcemia (Ca ≥10.5 mg/dL)
    • History of kidney stones with hypercalciuria
    • Sarcoidosis
    • Nephrolithiasis
    • Hypoproteinemia (Total protein ≤6.0 g/dL)
    • Severe renal impairment (eGFR < 30 mL/min)

14. Patients with severe neurological or psychiatric disorders that, in the investigator's judgment, are sufficient to affect the clinical trial outcomes (e.g., depression, dementia, delirium).

15. Patients who are breastfeeding or who, or whose partners, are planning to become pregnant during the clinical trial period.

16. Individuals who have participated in another clinical trial within 30 days prior to screening.

17. Patients with a history of bleeding-related or gastrointestinal diseases, as described below:

    • Evidence of active bleeding, bleeding diathesis, coagulopathy, or tumors involving major blood vessels.
    • Clinically significant peptic ulcers, gastrointestinal bleeding, gastrointestinal or non-gastrointestinal fistulas, perforations, intra-abdominal abscesses, signs or symptoms of gastrointestinal obstruction, requirement of parenteral hydration or nutrition, or a history of inflammatory bowel disease (IBD).
    • Evidence of free air in the abdomen not explained by paracentesis or recent surgical procedures.

18. Patients who have received biguanides (e.g., metformin) within 2 weeks prior to screening or are expected to require them during the clinical trial.

19. Patients requiring continuous systemic corticosteroid therapy (exceptions allowed as below):

    • Use of local corticosteroids such as intra-articular, intranasal, ophthalmic, or inhaled corticosteroids is permitted.
    • Temporary systemic corticosteroid use for treatment or prevention of contrast agent allergy or adverse events is allowed.

20. Patients with HIV or other severe diseases deemed by the investigator to make study participation inappropriate.

21. Patients who underwent drainage of ascites and/or pleural effusion within 14 days prior to screening.

22. Patients with hemoptysis (defined as ≥1/2 teaspoon of bright red blood per episode) within 14 days prior to screening.

23. Patients who underwent core biopsy or other minor surgical procedures (excluding vascular access device placement) within 3 days prior to the first administration of the investigational product.

24. Patients with significant, unhealed wounds, active ulcers, or untreated fractures.

25. Patients with a history of cerebrovascular accident (stroke), transient ischemic attack, or subarachnoid hemorrhage within 6 months prior to screening.

26. Patients with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

27. Any other condition deemed by the investigator to make the patient unsuitable for participation in the clinical trial.

    [Exclusion Criteria Applicable Only to Study 1]

28. Patients with a history of hypersensitivity to megestrol acetate or any of its components.

29. Patients who have been receiving continuous antithrombotic therapy (antiplatelet agents, oral anticoagulants, or a combination thereof) within 4 weeks prior to screening, or who are anticipated to require antithrombotic therapy during the study period.

30. Patients with diabetes mellitus.