1. Objective response rate (CR/PR). Measurement time: At enrollment, 4 weeks after the last dose of the second cycle, and at months 6, 9, and 12.
2. Overall survival (OS) (Time from patient enrollment to death, regardless of cause, or to the date of last reported death). Measurement time: month 12.
3. Progression-free survival (PFS) (Time from the start of treatment to the date of considered disease progression or death from any cause). Measurement time: month 12.
4. Duration of response (Time from the date the patient achieves a response with study treatment (CR/PR) to objective disease progression or death). Measurement time: up to month 12 in patients who achieve an objective response (CR/PR) with treatment. Immunological Evaluation
1. Expansion of effector T cell populations. Measurement time: baseline, 24 hours after the completion of cycles 1 and 2.
2. Natural killer (NK) cells. Measurement time: baseline, 24 hours after the completion of cycles 1 and 2.
3. Regulatory T cells (Tregs). Measurement time: baseline, 24 hours after the completion of cycles 1 and 2.
4. Memory subpopulations. Measurement time: baseline, 24 hours after the completion of cycles 1 and 2.
5. Activation parameters. Measurement time: baseline, 24 hours after the completion of cycles 1 and 2.
Pharmacokinetic parameters. The following will be performed in phase II:
1. Bioavailability-F (estimated value using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: After the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data block design with 4 patients per sample collection design, where each patient will have 14 draws.
2. Volume of distribution (V) (estimated using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: After the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data block design with 4 patients per sample collection design, where each patient will have 14 draws.
3. Elimination constant (k) (estimated using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: After the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data block design with 4 patients per sample collection design, where each patient will have 14 draws.
4. Maximum concentration (Cmax) (estimated using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: after the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data design in blocks of 4 patients per sample collection design, where each patient will have 14 samples drawn.
5. Half-life (T 1/2) (estimated using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: after the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data design in blocks of 4 patients per sample collection design, where each patient will have 14 samples drawn.
6. Plasma clearance (Cl) (estimated using the Monolix system, SAEM algorithm combined with Monte Carlo coding). Measurement time: After the first dose of cycle 1 and at the last dose of cycles 1 and 2, using a sparse data design in blocks of 4 patients per sample collection design where each patient will have 14 samples drawn. Safety
1. Adverse events-AEs (Occurrence of any AE [Yes, No], description [AE name], duration [time elapsed from start date to end date of AE], intensity [Mild, Moderate, Severe, life-threatening or disabling AE, AE resulting in death], severity [Severe/serious or Not Applicable (NP)], outcome [recovered, improved, persists, sequelae], treatment approach [no change, dose modification, temporary or permanent discontinuation of study treatment], causality [1. Definite, 2. Very likely, 3. Probable, 4. Possible, 5. Unrelated, 6. Unknown], treatment indicated for the AE [medicines indicated to counteract the AE], product batch [batch ID]). Measurement time: Every 1 or 4 hours as needed during product administration, at 4 weeks after the last administration, months 6, 9, and 12.
2. Laboratory-hematological tests (hemoglobin, hematocrit, leukogram with differential, and platelet count). Measurement time: Initial evaluation, at 4 weeks after the last administration, months 6, 9, and 12.
3. Laboratory-hemochemical tests (alkaline phosphatase, SGOT, SGPT, creatinine, total and direct bilirubin). Measurement: Baseline assessment, 4 weeks after the last dose, months 6, 9, and 12.
4. Vital signs (Blood pressure [mmg], Heart rate [min], temperature [0°C]). Measurement time: every 1 or 4 hours as needed during product administration, months 6, 9, and 12.
5. Cardiac function assessment (echocardiogram results). Measurement time: at enrollment, 4 weeks after the end of the last cycle.
6. Physical examination results (Each system will be evaluated as Normal, Abnormal [depending on the findings], Not Examined [if not performed]). Measurement time: before each dose and 1 hour after, months 6, 9, and 12.
7. Antibodies against the mutein (Presence or absence). Measurement time: baseline, 24 hours after the end of cycles 1 and 2.