Ensayos clínicos

Inclusion Criteria:

• Subject must sign the written ICF before any screening procedure.
• Subject must be aged ≥ 18 years (y) on the date of signing the informed consent.
• Subject must have histologically confirmed, unresectable, locally advanced or metastatic solid cancers.
  • In Part A, all HER2-positive solid cancers are eligible;
  • In Part B, HER2-positive breast, GEA and other HER2- positive solid cancers are eligible for the respective expansion groups.
• All subjects in both parts of the study must be HER2-positive in the latest tumor sample tested for HER2 (it is required that testing is done on a metastatic lesion in cases of metastatic cancers for subjects with metastatic disease), according to standard testing procedures. For the purpose of this study, HER2-positivity is defined as:
  • Tumors tested by IHC: must have an IHC status of 2+ or 3+, regardless of ISH result; OR
  • BC or GEA tumors tested by ISH only (no IHC available): must be HER2-positive.
  • Note: cancers other than BC and GEA must be tested via IHC and must have a status of 2+ or 3+, regardless of ISH result.
• Subject should be relapsed or refractory to existing therapy(ies) known to provide clinical benefit for the underlying cancer or have been intolerant of such therapies.
  • Subjects with HER2-positive BC per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines (Wolff et al, 2018) should have received at least 2 lines of HER2-directed therapy in the advanced setting and should have received at least 2 of the following: pertuzumab, trastuzumab emtansine, tucatinib or fam trastuzumab deruxtecan in either the early-stage or advanced setting. Subjects with tumors that are HER2 2+ by IHC and without gene amplification are not required to have received prior HER2-targeting therapy;
  • Subjects with HER2-positive gastric cancer per ASCO-CAP guidelines (Bartley et al, 2016) must have previously received trastuzumab or fam trastuzumab deruxtecan or have been intolerant of such therapy. Subjects with tumors that are HER2 2+ by IHC and without gene amplification are not required to have received prior HER2-targeting therapy.
• Subject must have at least 1 measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (APPENDIX D: Eisenhauer et al, 2009).
  • Subjects with evaluable disease only may be included in the dose escalation phase.
• Subject must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (APPENDIX B).
• Subject must have a life expectancy of at least 3 mo. 9. Subject must have adequate bone marrow function, as determined by:
  • ANC ≥ 1,000/mm^3;
  • Platelet count ≥ 75,000 mm³; and
  • Hemoglobin ≥ 8.0 g/dL. Red blood cell transfusion within 2 wk of study treatment start is allowed if hemoglobin levels remain stable (i.e., do not decrease by > 1 g/dL by C1D1).
• Subject must have adequate kidney function, as determined by: a. Creatinine clearance ≥ 50 ml/min either measured or estimated using the Cockcroft-Gault formula.
• Subject must have adequate hepatic function, as determined by:
  • Total bilirubin ≤ 1.5 x ULN, or ≤ 3 x ULN for subjects with Gilbert’s Syndrome; and
  • AST ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis); and
  • ALT ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis).
• Subject must have adequate serum albumin, as determined by:
  • Albumin ≥ 2.5 g/dL.
• Subject must have adequate coagulation, as determined by:
  • international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN; and
  • partial thromboplastin time ≤ 1.5 x ULN.
• Subject must have adequate cardiac function, as determined by:
  • LVEF ≥ 55% assessed by ECHO (preferred), or multigated acquisition (MUGA) scan; and
  • QTcF ≤ 480 ms for women and QTcF ≤ 450 ms for men (average from 3 QTcF values on the triplicate 12-lead electrocardiogram) at baseline.
  • NOTE: Subjects with right bundle branch block and LVEF ≥ 55% will be eligible for participation.
• Women of reproductive potential must have a negative pregnancy test during the screening period within 72 h before the start of treatment. Women not of reproductive potential are female subjects who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
• Subjects of reproductive potential must agree to either abstain continuously from heterosexual intercourse or to use a highly effective method of birth control between signing the informed consent until 90 d after last study treatment. The Investigator or Delegate should advise the subject to use a double barrier method to achieve adequate contraception. The following birth control methods will be considered as adequate:
  • Condoms (male or female) with a spermicidal agent;
  • Diaphragm or cervical cap with spermicide;
  • Condom with diaphragm;
  • Intrauterine device;
  • Hormone-based contraception: Established use of oral, injected, or implanted hormonal methods of contraception;
  • Vasectomy (for a male subject or male partner of a female subject).

Exclusion Criteria: 

• History or current evidence of neoplastic disease that is histologically distinct from the tumor under study, except cervical carcinoma in situ, superficial noninvasive bladder tumors, curatively treated Stage I-II non-melanoma skin cancer, or any other previous cancer curatively treated less than 2 y prior to enrollment in this study. Subjects with any other active malignancy may only be enrolled after discussion and approval by the Sponsor.
• Current evidence of new or growing central nervous system (CNS) metastases during screening. Subjects with known CNS metastases will be eligible if they meet all the following criteria:
  • Had radiotherapy or another appropriate therapy for the CNS metastases;
  • Have no neurological symptoms > Grade 2, with approval by the Medical Monitor;
  • Have stable CNS disease on the Computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 wk before signing the informed consent compared with prior neuro-imaging;
  • Do not require steroid therapy.
• Current evidence of CTCAE Grade > 1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria. Subjects with Grade 2 neurologic symptoms or other toxicities that are asymptomatic or adequately managed with stable medication may be eligible with approval by the Medical Monitor.
• Current evidence of incomplete recovery from surgery or radiotherapy at screening, or planned surgery or radiotherapy from the start of treatment until the STFU Visit, except minor elective surgery deemed acceptable by the Investigator.
• History or current evidence of significant (CTCAE Grade ≥ 2) infection or wound within 2 wk before the start of treatment.
• history or current evidence of significant cardiovascular disease before the start of treatment, but not limited to the following conditions:
  • High sensitivity troponin I or T > ULN at screening;
  • Angina pectoris requiring anti-anginal medication, (chest pain: CTCAE Grade ≥ 2) or clinically significant valvular disease;
  • Myocardial infarction within 12 mo prior to the start of treatment;
  • Arterial thrombosis or pulmonary embolism within ≤ 6 mo before the start of treatment;
  • Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥ 2), non-malignant pleural effusion (CTCAE Grade ≥ 2) or malignant pleural effusion (CTCAE Grade ≥ 3) (subjects with pleural effusion that is manageable and stable > 3 mo prior to study are eligible);
  • Left bundle branch block;
  • History of Grade ≥ 2 symptomatic congestive heart failure or New York Heart Association (NYHA): Class ≥ II;
  • High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia [CTCAE Grade ≥ 2] [ventricular tachycardia], or higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 (Mobitz 2) or third degree AV-block]).
• Current evidence of active, uncontrolled hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) (evidenced by detectable viral load by polymerase chain reaction or acquired immunodeficiency syndrome (AIDS) related illness.
  • Serology and virology measurements are not required to be performed at screening, but any previously-reported results should be used for eligibility purposes. Subjects with no previously reported results are eligible in the absence of history of HBV/HCV/HIV. Investigators will test per their discretion;
  • Subjects with a history of treated hepatitis C and non-quantifiable HCV-ribonucleic acid may be enrolled;
  • Subjects on treatment for HBV and/or HIV will be eligible if they have undetectable viral load.
  • Subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/µL may be enrolled;
  • Subjects taking atazanavir should be considered for alternate therapy given the risk of cardiac conduction abnormalities.
• Known or suspected hypersensitivity to the study drug or excipients contained in the study drug formulation.
• Current evidence of hypersensitivity requiring systemic steroids at doses > 20 mg/d prednisone equivalent.
• History or current evidence of any other medical or psychiatric condition or addictive disorder, or laboratory abnormality that, in the opinion of the Investigator, will increase the risks associated with study participation, or require treatments that will interfere with the conduct of the study or the interpretation of study results.
• Current evidence of ≥ Grade 2 underlying pulmonary disease.
• Women who are pregnant or breastfeeding.
• Subjects with unintentional weight loss greater than 10% of their body weight over the preceding 3 mo or less.
• Therapeutic anticoagulation for a thromboembolic event within 2 wk before the start of treatment (prophylactic anticoagulation is allowed).
• Received systemic therapy for the cancer under study or any investigational drug within 4 wk before the start of treatment.
• Received immunosuppressive agents or other prescribed corticosteroids at doses ≥ 20 mg prednisone equivalent per d within 2 wk before the start of treatment.
• For Part A (dose escalation phase): Received chemotherapy with doxorubicin (or another anthracycline) at any time. For Part B (dose expansion phase): Received chemotherapy with anthracycline or anthracenedione agents at the doxorubicin equivalent cumulative dose (sum total for all agents combined) of 550 mg/m^2 body surface area, or a lower total doxorubicin equivalent cumulative dose that, in the opinion of the Investigator, would increase the risk of cardiomyopathy in this study, or subjects who have received mitoxantrone at cumulative doses considered to increase the risk of cardiomyopathy. For subjects who have received a cumulative dose of an anthracycline of more than 300 mg/m^2 , approval must first be obtained from the Medical Monitor.
• Received granulocyte colony–stimulating factor or granulocyte-macrophage colony–stimulating factor for the treatment of leukopenia within 2 wk before the start of treatment.

Eligibility last updated 8/11/21. Questions regarding updates should be directed to the study team contact.