ML-016 in Advanced Cancer With Lung and/or Liver Involvement

ML-016 will be administered intravenously as a monotherapy to assess safety, tolerability, pharmacokinetics (PK), and anti-tumor activity in participants with advanced/metastatic solid tumors with lung and/or liver involvement. The involvement of the lung and/or liver can involve primary or metastatic disease.

Participants eligible for treatment include those whose disease is refractory to standard therapeutic options or for which no standard measures with curative intent or likelihood of disease control are available, or such measures are not acceptable to the participant.

Participants will be administered ML-016 on Day 1 of each 21-day cycle. Treatment may continue until the participant's disease worsens or another treatment discontinuation criterion is met.

Phase 1 will be a standard dose escalation design, and Phase 2 will be a dose expansion design evaluating two doses in disease-specific cohorts.

Inclusion criteria

• Age ≥18 years old on the day of signing the consent form
• Histopathological or cytological confirmed diagnosis of advanced (locally advanced or metastatic) solid malignancy which is refractory to standard therapeutic options or for which no standard measures with curative intent or likelihood of disease control are available, or such measures are not acceptable to the participant.
• Eastern Cooperative Oncology Group Performance Status ≤1
• The participant has adequate baseline hematologic function, as demonstrated by the following:

• Hemoglobin ≥8.0 g/dL ,
• Neutrophil count ≥1.5 x 109/L,
• Platelets ≥75 x 109/L
• The participant has adequate baseline kidney function, as demonstrated by the following:

• Serum creatinine ≤1.5 x ULN, and/or
• Calculated creatinine clearance ≥60 ml/min using the Cockroft-Gault formula or per institutional standard method
• The participant has adequate baseline liver function, as demonstrated by the following:

• Total bilirubin <1.5 x ULN (except for participants with Gilbert syndrome), or
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤3 x ULN, or for participants with liver involvement AST/ALT <5 x ULN
• Measurable disease using RECIST v 1.1 for solid tumors
• Evidence of tumor in the lung and/or liver based on imaging studies.
• For participants with lung metastases, adequate pulmonary function: FEV1, FVC and DLCO ≥50% predicted (corrected for hemoglobin) and no oxygen dependency.
• For participants with liver metastases, adequate liver function with less than 70% liver involvement as measured by imaging (i.e. CT, MRI, PET/CT, or ultrasound).
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

• Documented to be surgically sterile or postmenopausal (amenorrhea 24 months and follicle-stimulating hormone [FSH] ≥30 mIU/mL), OR
• Practicing true abstinence for at least 28 days prior to study treatment until 120 days after the last dose of study treatment and having a negative serum urine pregnancy test within 72 hours before initiating treatment, OR
• Using 2 forms of highly effective contraception, including 1 physical barrier (condom or diaphragm) plus another method, such as adequate hormonal method (eg, contraceptive implants, injectables, oral contraceptives) or nonhormonal methods (eg, intrauterine device, spermicidals) from screening or at least 28 days prior to study treatment administration (whichever is earlier) until 120 days after the last dose of study treatment and having a negative serum urine pregnancy test within 72 hours before initiating treatment.
• Male participants with female partners of childbearing potential may be enrolled if they are:

• Documented to be surgically sterile (vasectomy), OR
• Practicing true abstinence until 28 days after the last dose of study treatment, OR
• Using 2 effective methods of contraception including one barrier method (e.g., condom with spermicide and contraception by female partner) for the duration of time on the study and for 120 days after administration of the last dose of study treatment, unless their partners are infertile or surgically sterile.
• Minimum life expectancy of 3 months.
• Ability to read and understand the informed consent form and willingness and ability to give informed consent and demonstrate comprehension of the trial before undergoing any trial assessments.
• The participant can adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
• The participant allows tissue biopsy to be available (archive or fresh tissue) unless approved by the Sponsor.

Exclusion criteria

• Participants must not receive prior anticancer therapy or prior investigational therapy within 3 weeks or 5 half-lives, whatever is shorter, or radiation therapy within 3 weeks, and must not undergo major surgery within 4 weeks prior to initiation of treatment on protocol. Palliative radiation therapy is allowed (no palliative radiation may be given to RECIST lesions).
• The participant must have recovered from all AEs due to previous therapies to Grade ≤1 or baseline. Participants with Grade ≤2 alopecia and/or neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. Prior toxicities that resulted in laboratory abnormalities should have resolved to Grade ≤1 unless a higher-grade abnormality is allowed by the inclusion criteria. If medical therapy is required for the treatment of a laboratory abnormality, the dose and laboratory value(s) should be stable.
• Symptomatic brain metastasis or leptomeningeal disease requiring treatment. Participants with treated brain metastasis must have stable disease for at least 4 weeks, as evidenced by brain imaging, and the participant must have been asymptomatic off steroids for at least 2 weeks.
• Cardiac conditions: hypertension (BP > 160/100) despite optimal therapy, ventricular arrhythmias, significantly impaired cardiac function such as unstable angina pectoris, congestive heart failure with New York Heart Association (NYHA) class III or IV, myocardial infarction within the 6 months prior to trial entry; signs of pericardial effusion, serious arrhythmia (including QTc prolongation of >470 ms and/or pacemaker), or prior diagnosis of congenital long QT syndrome
• Left ventricular ejection fraction <50% or below the lower limit of institutional normal (whichever is higher) on screening echocardiogram.
• History of anthracycline induced cardiotoxicity
• History of another primary malignancy (other than basal cell or squamous cell carcinoma, or in situ carcinoma) within 2 years prior to consent.
• Pregnancy or current breastfeeding or planning to breastfeed.
• Previous treatment with total cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones (≥450 mg/m2).
• Hypersensitivity to doxorubicin, any of its excipients, or other anthracyclines or anthracenediones or compounds of similar chemical or biologic composition as the study drug.
• The participant has a history of (non-infectious) pneumonitis or interstitial pulmonary disease that required corticosteroids within the past 3 months or has current pneumonitis or interstitial pulmonary disease.
• The participant has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the participant at significant risk for pulmonary complications during the study.
• The participant has an active autoimmune disease that required systemic treatment in the past. Participants who have not required systemic treatment for at least two years may be enrolled if permission is provided after discussion with the Medical Monitor (replacement therapy, e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment, and is allowed).
• Concurrent severe and/or uncontrolled medical disease that could compromise participation in the study (i.e., uncontrolled diabetes, severe infection requiring intravenous antibiotics, severe malnutrition, chronic severe liver or renal disease).
• The participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.