A Trial Evaluating the Anti-tumor Activity of Antibody-based Therapies in Metastatic Cancer Patients (MOST-Express)

Inclusion Criteria:

• I1 . Male or female patient ≥18 years of age at time of informed consent form signature.

• I2 . Patient with histology confirmed diagnosis of advanced inoperable or metastatic solid tumor including:

  • Cohort A: Pan-rare tumor as per ESMO definition, with the incidence of below 6 cases / 100 000 p/year (except with T-DXd approvals).
  • Cohort B: Non-small cell lung cancer (NSCLC)
  • Cohort C: Urothelial cancer.
  • Cohort D: Pan-frequent tumors i.e., non rare tumor types, except with T-DXd approvals and reimbursement in France

• I3 . Patients with documented HER2 tumor expression, validated by the MTB (virtual possible), assessed locally by:

  • Stage I: IHC with 3+ using PATHWAY/VENTANA anti-HER2/neu (4B5) and scored using current ASCO/College of American Pathology guidelines for scoring HER2 in gastric cancer; and/or

  • Stage II (conditional depending of Stage I results) patients must meet at least one of the following biomarker eligibility criteria*: - HER2 IHC 3+ using the same criteria used in Stage I; or - RNASeq-derived biomarker positivity defined as gene expression >90th percentile (z-score ≥0.9).

    • Patients meeting either criterion is sufficient for eligibility. Positivity for both biomarkers is not required. Patients with discordant HER2 IHC and RNASeq derived biomarker results remain eligible for enrollment, provided that at least one biomarker meets the predefined positivity criteria. Tumor sample used for this screening will be a representative formalin-fixed paraffin-embedded (FFPE) sample of the primary or metastatic tumor tissue (resection or biopsy), the most recent tumor sample must be selected and present ≥30 % of tumor cells. This tumor sample with an associated pathology report must be sent to the sponsor within 14 days following C1D1.

• I4 Patients with confirmed documented disease progression after at least one line of standard therapy for the eligible tumor types listed in I2.

• I5 . Patients with evaluable disease as per RECIST V1.1

• I6 . Patients with ECOG PS 0-1

• I7 . Patient with tumor lesion visible by medical imaging and accessible to repeatable percutaneous or endoscopic sampling that permits core needle biopsy without unacceptable risk of a significant procedural complications.

• I8 . Adequate bone marrow and end-organ function, defined by the following laboratory test results performed within 14 days before C1D1:

  • Peripheral absolute neutrophil count (ANC) ≥1.5 x 109 /L (G-CSF administration is not allowed within 7 days prior to screening assessment)
  • Platelet count ≥ 100 x 109/L (Platelet transfusion is not allowed within 7 days prior to screening assessment)
  • Hemoglobin ≥ 9.0 g/dL (without transfusion within 7 days)

Renal and hepatic function :

• Serum creatinine or creatinine clearance according to CKD-EPI

  o ≤ 1.5 X upper limit of normal (ULN) OR ≥ 30 mL/min/1.73m2

• Total bilirubin

  o ≤ 1.5 x ULN if no liver metastases or < 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.

• Aspartate aminotransferase (ASAT) and Alanine aminotransferase (ALAT) ≤ 3 X ULN (up to 5x ULN in case of liver metastases)

• ≤ 1.5 × ULN, except for subjects receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have INR/PT within the therapeutic range as deemed appropriate by the investigator

  - I9 Patient with adequate washout period for prior anti-cancer treatment before to C1D1:

• Major surgery ≥ 4 weeks

• Radiation therapy including palliative stereotactic radiation to chest: ≥ 4 weeks

• Palliative stereotactic radiation therapy to other anatomic areas : ≥ 2 weeks

• Chemotherapy, retinoid therapy, hormonal therapy:≥ 3 weeks or 5 half-lives whichever is shorter.

• Kinase inhibitors :≥ 2 weeks or 5 half-life whichever is shorter

• TKIs approved for treatment of NSCLC: ≥ 1 week

• Antibody-based anticancer therapy:≥ 4 weeks

• Cell-free and concentrated ascites reinfusion therapy (CART), peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion :≥ 2 weeks

• Live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) :>30 days prior to C1D1

  • I10 Patient with LVEF ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before C1D1
  • I11 Women of childbearing potential must have a negative serum pregnancy test at the screening visit (within 3 days of C1D1) and must agree to use one highly effective contraceptive measure starting with the screening visit through 7 months after the last dose of T-DXd. Female patients must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrolment in this study.
  • I12 Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through 4 months after the last dose of T-DXd. Male subjects must not freeze or donate sperm starting at enrolment and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study.
  • I13 Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.
  • I14. Patients must be covered by a medical insurance.

Exclusion Criteria:

• E1 Patients with medical history of myocardial infarction (MI) or symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) within 6 months before C1D1

• E2 Patients with corrected QT interval prolongation > 470 msec (females) or >450 msec (males) based on average of the triplicate 12-lead ECG at screening.

• E3 Patients with respiratory function impairment:

  1. 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, or
  2. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., Pulmonary emboli within three months of C1D1, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.), or
  3. Prior complete pneumonectomy.

• E4 Patients with spinal cord compression or clinically active CNS metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive brain metastases may be included in the study. Patients 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 brain radiotherapy and C1D1.

• E5 Patients with other primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumor curatively treated

• E6 Patients with history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product, to other monoclonal antibodies.

• E7 Patients with uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.

• E8 Patients with active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C infection.

• E9 Patients with ongoing toxicities of Grade >1 (excluding alopecia) from previous anticancer therapy, with the following exceptions: chronic, stable Grade 2 toxicities (defined as no worsening to Grade > 2 for at least 3 months prior to C1D1 and managed with standard of care treatment) related to previous anticancer therapy, such as peripheral sensitive neuropathy and fatigue.

• E10 Residual toxicities from prior ICI treatment: Grade 1 or Grade 2 endocrinopathies. If required steroids administration, the participants eligibility can be discussed on individual basis with the Sponsor.

• E11 Prior treatment with any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I.

• E12 Patients with 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 patient's participation in the clinical study or evaluation of the clinical study results.

• E13. Pregnant or lactating women