A Phase I Study of SIM0505 in Participants With Advanced Solid Tumors

A Phase I First-in-human, Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of SIM0505 in Adult Participants With Advanced Solid Tumors

This is an open-label, multicenter phase 1 study to evaluate the safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of SIM0505 in Adult Participants with Advanced Solid Tumors

Inclusion Criteria:

1. Written informed consent is obtained prior to any procedures that are not considered standard of care.

2. ≥18 years of age.

3. In Part 1:

   1. Participants with histologically or cytologically confirmed advanced solid tumors, who have failed or are ineligible for standard of care therapies.
   2. Have progressed on at least one prior systematic anti-tumor regimen, and presence of at least one evaluable lesion according to RECIST Version 1.1. Measurable lesions are required in the backfill period.
   3. In the backfill period, eligible tumor types are limited to high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, USC, clear cell RCC, papillary RCC and adenocarcinoma of NSCLC without actionable mutation of epidermal growth factor receptor (EGFR). For participants with NSCLC, presence of CDH6 expression through immunohistochemical examination of tumor tissue by central laboratory is required.

4. In Part 2: Participants must have a diagnosis of specific type of metastatic or locally advanced solid tumors and have progressed on or cannot benefit from the most recent systematic anti-tumor regimen (unless otherwise specified), with presence of at least one measurable lesion according to RECIST Version 1.1.

   Platinum-resistant ovarian cancer cohort:

   1. Participants with histologically or cytologically confirmed high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
   2. Have platinum-resistant disease, defined as: participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a best response of CR or PR, and then progressed between >90 days and ≤180 days after the date of the last dose of platinum; participants who have received ≥2 lines of platinum therapy must have progressed ≤180 days after the date of the last dose of platinum.
   3. At least one line of therapy containing anti-VEGF therapy (e.g., bevacizumab or suvemcitug or their biosimilar), unless the participant is not eligible for treatment with anti- angiogenic treatment due to precautions/intolerance. Has had prior poly-ADP ribose polymerase (PARP) inhibitors for subjects with documented breast cancer gene (BRCA) mutation (germline and/or somatic), unless the subject is not eligible for treatment with a PARP inhibitor. Has had prior treatment with mirvetuximab soravtansine for participants with documented high folate receptor alpha expression, unless the subject is not eligible for treatment with mirvetuximab soravtansine due to precautions/intolerance, or if the treatment is not approved or available locally. In the PROC cohort, topoisomerase inhibitor payload ADC-pretreated participants should have received at least one prior topoisomerase inhibitor payload ADC.

   Renal cell carcinoma cohort:

   1. Participants with histologically- or cytologically-confirmed clear cell RCC or papillary RCC.
   2. For clear cell RCC: Participants who have progressed on or after systemic treatment including a programmed cell death protein 1 or programmed death ligand 1 (PD-1/PD-L1) checkpoint inhibitor and a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI), either given concurrently or in separate lines of therapy.
   3. For papillary RCC: Participants without any prior systemic treatment is acceptable.

   Uterine serous carcinoma cohort:

   1. Participants with histologically- or cytologically-confirmed USC.
   2. Have progressed on or after systemic treatment that contained platinum-based chemotherapy.

   Non-Small Cell Lung Cancer cohort:

   1. Participants with histologically- or cytologically-confirmed adenocarcinoma of NSCLC without actionable mutation of EGFR.
   2. Presence of CDH6 expression through immunohistochemical examination of tumor tissue.
   3. For participants without actionable mutations: Have progressed on or after systemic treatment including anti-PD-1/PD-L1 antibody and platinum-based chemotherapy, either given concurrently or in separate lines of therapy. Progression within 6 months after completion of adjuvant therapy is considered failure of first-line therapy.
   4. For participants with actionable mutations other than EGFR: Have failed at least one established standard anti-cancer targeted therapy, anti-PD-1/PD-L1 antibody and platinum-based chemotherapy (PD-1/PD-L1 and chemotherapy either given concurrently or in separate lines of therapy) or in the opinion of the Investigator have been considered ineligible for a particular form of standard of care therapy on medical grounds.

5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

6. Life expectancy of ≥12 weeks.

7. Have adequate organ function as indicated by the laboratory values listed within the protocol.

8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the start of study treatment. WOCBP or male participants who have sexual relations with WOCBP are required to use highly effective contraceptive methods, and agree to refrain from donating sperm/egg from signing of informed consent through 180 days after the last dose of study treatment.

9. Able to provide tumor tissue sample (archival or newly obtained core or excisional biopsy). For Part 1: At biomarker-screening (for NSCLC) or screening (for non-NSCLC) visit of a tumor lesion not previously irradiated for CDH6 testing.

For Part 2: Willing to undergo fresh tumor biopsy at biomarker-screening visit (for NSCLC) and screening visit (non-NSCLC) from a lesion that can be biopsied at an acceptable clinical risk as judged by the investigator.

Exclusion Criteria:

1. For Part 2: has clear cell, mucinous or sarcomatous histology, mixed tumors containing any histology, or low-grade/borderline ovarian cancer; mixed nonsmall cell and small cell carcinoma, or adenosquamous cell lung cancer with an adenocarcinoma component <50% (the participant is eligible if the adenocarcinoma component is ≥50%).
2. For Part 2: Participants with primary platinum refractory ovarian cancer, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy.
3. Any other malignancy within 2 years prior to the first dose of the study treatment except for localized cancers that are considered to have been cured and in the opinion of the Investigator present a low risk for recurrence.
4. Known untreated CNS metastases and/or leptomeningeal metastases. Participants are eligible if CNS metastases have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment). In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to the first dose of study treatment. Imaging performed within 28 days prior to the first dose of study treatment must document radiographic stability of CNS lesions and be performed after completion of any CNS-directed therapy.
5. History of bowel obstruction within 3 months prior to the first dose of study treatment.
6. Known psychiatric disorder or drug abuse that would interfere the study requirements.
7. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring drainage or medical intervention within 4 weeks before the first dose of study treatment.
8. Any active infection requires systemic treatment via intravenous infusion within 2 weeks prior to the first dose of study treatment.
9. History of non-infectious pneumonitis that has required a course of oral or intravenous steroids to assist with recovery, or interstitial lung disease (ILD) or severe obstructive pulmonary disease.
10. Prior exposure to other CDH6-targeted agents.
11. Prior exposure to an ADC with a topoisomerase I inhibitor payload (e.g., raludotatug deruxtecan/DS-6000) for all cohorts except for the topoisomerase inhibitor payload ADC-pretreated participants in PROC cohort.
12. Has not recovered (i.e., to CTCAE version 5.0 Grade 1 or to baseline) from previous anticancer therapy-induced AEs. Grade ≤2 AEs with no impact on participant safety are exceptions to this criterion and may qualify for the study.
13. Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of first dose of SIM0505.
14. Major surgery within 2 weeks of receiving the first dose of study treatment.
15. Has received prior anti-cancer therapies within the following time frames prior to the first dose of study treatment: previous cytotoxic therapy, anticancer targeted small molecules (e.g., tyrosine kinase inhibitors), hormonal agents within 2 weeks; anti-cancer antibody or ADC within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study treatment; Chinese medicines/herbal preparations with anticancer indication taken within 2 weeks; and/or radiation therapy within 2 weeks for focal radiation or within 4 weeks for wide-field radiation.
16. Use of any live vaccine therapy within 4 weeks prior to the first dose of study treatment.
17. Administration of strong or moderate CYP3A4 inhibitors or drugs with known risk of Torsades de Pointes (TdP) ≤ 7 days or 3 half-lives (whichever is longer) prior to the first dose of SIM0505.
18. Known human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).
19. Active hepatitis B or hepatitis C infection.
20. Participants with clinically significant cardiovascular diseases.
21. History of allogeneic organ transplantation or graft-versus-host disease.
22. Known hypersensitivity to study drug or any of the excipients.
23. Participant is pregnant or breastfeeding.
24. Other conditions that researchers consider inappropriate for inclusion.