Ensayos clínicos

Inclusion Criteria:

• Sign and date the ICF prior to the start of any study- specific qualification procedures.
• Adults ≥ 18 years (if the legal age of consent is > 18 years old, then follow local regulatory requirements).
• Has pathologically documented NSCLC that:
  • Is stage IIIB or stage IV NSCLC disease at the time of enrollment (based on the American Joint Committee on Cancer, Eighth Edition);
  • Has 1 or more of the following documented activating tumor genomic alterations*: EGFR**, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET.

*  Overexpression of any of the above, in the absence of activating mutations, is NOT sufficient for enrollment.
** These patients should be evaluated for presence of EGFR T790M mutation after relapse/progression on/after most recent anti-EGFR TKI, unless already known to carry this mutation. Subjects with EFGR mutations (regardless of T790M status) should comprise no less than 40% and no more than 50% of subjects by the conclusion of study enrollment.

• Has documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
• Subject must meet the following for advanced or metastatic NSCLC:
  • Has been treated with at least one but no more than two cytotoxic agent-containing therapy in the metastatic setting:
  • One platinum-containing regimen (either as monotherapy or combination therapy);
  • May have received up to one additional line of cytotoxic agent-containing therapy;
  • Those who received a platinum-containing regimen as adjuvant therapy for early stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for relapsed/progressive disease;
  • May have received up to one checkpoint inhibitor (CPI)-containing regimen (may be in combination with a cytotoxic agent as part of a regimen described in 5a above or as an additional CPI regimen without a cytotoxic agent); c. Has been treated with one or more lines of non-CPI targeted therapy that is locally approved for the subject’s applicable genomic alteration at the time of screening; OR one or more of the agents specified in the table below; i. Those who received a targeted agent as adjuvant therapy for early stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of targeted therapy for the same genomic alterations (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease. ii. Subjects who have been treated with a prior TKI must receive additional targeted therapy, if clinically appropriate, for the applicable genomic alterations, or the subject will not be allowed in the study.
• Must undergo a mandatory pre-treatment tumor biopsy procedure. OR If available, a tumor biopsy that was recently collected (within 3 months of screening) after completion of the most recent anticancer treatment regimen and that has a minimum of 10 × 4 micron sections or a tissue block equivalent of 10 × 4 micron sections may be substituted for the mandatory biopsy collected during screening. Note: Results from this biopsy will not be used to determine eligibility for the study.
• Archival tumor tissue from initial diagnosis is required, to the extent that archival tumor tissue is available.
• Has measurable disease based on local imaging assessment using RECIST v1.1.
• Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at screening.
• Within 7 days before Cycle 1 Day 1, has adequate bone marrow function defined as:
• Platelet count ≥ 100,000/mm^3 (platelet transfusion is not allowed within 1 week prior to screening assessment);
• Hemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment);
• Absolute neutrophil count ≥1500/mm3 (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to screening assessment).
• Within 7 days before Cycle 1 Day 1, has:
  • Adequate hepatic function, defined as:
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) or AST/ALT ≤ 5.0 x ULN if transferase elevation is due to liver metastases); AND
  • Total bilirubin (TBL) ≤ 1.5 × ULN or (1.5 × ULN and ≤ 3 × ULN and any AST.
  • Note: After a maximum of 9 subjects with moderate hepatic dysfunction have been enrolled, subsequent subjects with moderate hepatic dysfunction will be excluded.
• Within 7 days before Cycle 1 Day 1, has adequate renal function, including mild or moderate renal function, defined as:
  • Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft-Gault equation.
• Has a left ventricular ejection fraction (LVEF) ≥ 50% by either an ECHO or MUGA scan within 28 days before Cycle 1 Day 1.
• Has adequate blood clotting function defined as international normalized ratio/prothrombin time and either partial thromboplastin or activated partial thromboplastin ≤ 1.5 × ULN.
• If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at screening and must be willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 7 months following the last dose of study drug. Females of non-childbearing potential are defined as pre-menopausal females with a documented tubal ligation or hysterectomy, or postmenopausal (defined as 12 months of spontaneous amenorrhea [in questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 mIU/mL and estradiol < 40 pg/mL/147 pmol/L is confirmatory]). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• If male, the subject must be surgically sterile or must use a condom in addition to highly effective birth control if their partners are of reproductive potential upon enrollment, during the Treatment Period, and for 4 months after the final dose of study drug administration.
• Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered before enrollment in the study.
• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration. Preservation of ova should be considered prior to enrollment in the study.
• Be willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
• Has a life expectancy ≥ 3 months based on investigator’s opinion.

Exclusion Criteria:

• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment. Note: A CT or magnetic resonance imaging (MRI) scan of the brain at baseline is required for all subjects. For those subjects in whom central nervous system (CNS) metastases are first discovered at the time of screening, the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging at least 4 weeks later (in which case, repeat of all screening activity may be required).
• Has leptomeningeal carcinomatosis.
• Prior treatment with:
  • An ADC containing a chemotherapeutic agent targeting topoisomerase I;
  • TROP2-targeted therapy.
• Uncontrolled or significant cardiovascular disease, including:
  • Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 milliseconds (msec) for females or >450 msec for males (based on the average of screening triplicate 12-lead ECG determinations);
  • History of myocardial infarction within 6 months prior to Cycle 1 Day 1;
  • History of uncontrolled angina pectoris within 6 months prior to Cycle 1 Day 1;
  • Symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) at screening. Subjects with a history of Class II to IV CHF prior to screening must have returned to Class I CHF and have LVEF ≥ 50% (by either an ECHO or MUGA scan within 28 days of Cycle 1 Day 1) in order to be eligible;
  • History of serious cardiac arrhythmia requiring treatment;
  • LVEF < 50% by ECHO or MUGA scan within 28 days before Cycle 1 Day 1;
  • Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) within 28 days before Cycle 1 Day 1.
• Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
• Clinically significant corneal disease.
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
  • Note: Subjects with localized fungal infections of skin or nails are eligible.
• Has known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ counts/levels > 250, no history of AIDs-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications. If an HIV infection meets the above criteria, monitoring of the subjects’ viral RNA load as well as the CD4+ count levels would be important. Subjects should be tested for HIV prior to Cycle 1 Day 1 if required by local regulations or Institutional Review Board (IRB)/Ethics Committee (EC).
• Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1.
  • Subjects with past or resolved HBV infection are eligible if:
    • Hepatitis B surface antigen (HBsAg) is negative and hepatitis B core antibody (anti-HBc) is positive; OR
    • HBsAg is positive and the HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases values (in the absence of liver metastasis); OR
    • HBsAg is positive and the HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation for subjects with liver metastasis and abnormal transaminases with a result of AST/ALT < 3 × ULN.
  • Subjects with a history of hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer).
• Has other primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥ 3 years.
• Concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator.
• Toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet improved to NCI-CTCAE version 5.0 Grade ≤ 1 or baseline.
  • Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to Cycle 1 Day 1 and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, comprised of (including, but not limited to):
  • Chemotherapy-induced neuropathy;
  • Fatigue.
  • Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include:
  • Hypothyroidism/hyperthyroidism;
  • Type I diabetes;
  • Hyperglycemia;
  • Adrenal insufficiency;
  • Adrenalitis;
  • Skin hypopigmentation (vitiligo).
• Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80).
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Is pregnant or breastfeeding or planning to become pregnant.
• Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
• Psychological, social, familial, or geographical factors that would prevent regular follow-up.
• Otherwise considered inappropriate for the study by the investigator.

Eligibility last updated 12/16/21. Questions regarding updates should be directed to the study team contact.