MC# 22-09 - A Phase I, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antitumor Activities of CS5001, an Anti-ROR1 Antibody Drug Conjugate, in Patients with Advanced Solid Tumors and Lymphomas
Disease Type(s): Lymphoma, Solid Tumor
Drug Classification(s): Targeted Therapy, Antibody Drug Conjugate
Molecular Target(s): ROR1
Mechanism of Action
CS5001 is a highly differentiated Antibody Drug Conjugate targeting ROR1. ROR1 is expressed across a variety of cancers, and may play an important role in oncogenesis by activating cell survival signaling events.
In this study, the sponsor and investigators want to learn:
- How much of CS5001 can be given with an acceptable level of side effects
- About the safety and tolerability of CS5001
- If the body’s immune system has a response to CS5001
- The effects of CS5001 (good and bad)
- How much of CS5001 is absorbed into the blood and how fast it is removed
- Patients must have progressed on or been intolerant to available standard therapies that are known to provide clinical benefit. Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line standard of treatment unless such treatments were completed less than 6 months prior to the current tumor recurrence.
- Phase Ia:
- a. Solid tumor: Pathologically confirmed, unresectable advanced solid tumor with disease progression on or after at least 1 line of prior systemic therapy. Preferred tumor types include breast, lung, gynecologic, prostate, skin, adrenal, testicular, colon, bladder, pancreatic, gastric, kidney, cholangiocarcinoma, and esophageal cancers.
- b. Lymphoma: Pathologically confirmed Hodgkin and non-Hodgkin B-cell lymphoma as defined per 2016 WHO classification, with disease progression on or after at least 2 lines of prior systemic therapy
- Patients with indolent lymphomas must be candidates for systemic treatment in the judgment of the investigator
- Patients with relapse or refractory classical Hodgkin lymphoma must have received brentuximab vedotin and at least one checkpoint inhibitor
- Phase Ib:
- c. Arm A (MCL):
- i. Pathologically confirmed mantel cell lymphoma (MCL), with documentation of either overexpression of cyclin D1 or presence of t(11;14)
- ii. Relapse or refractory disease following at least two prior lines of systemic therapy. Prior therapy must have included Bruton’s tyrosine kinase inhibitor (BTKi)
- d. Arm B (DLBCL): Pathologically confirmed DLBCL not otherwise specified (NOS) as defined per 2016 WHO classification. Patients with transformed lymphomas are permitted.
- i. Relapse or refractory disease following at least two prior lines of systemic therapy
- e. Arm C (TNBC):
- i. Pathologically confirmed advanced triple-negative breast cancer, who have progressive disease on or after at least 2 lines of systemic therapy for advanced disease
- ii. Positive ROR1 expression in baseline tumor tissue determined by a central IHC assay with any cytoplasmic or membranous staining at any intensity on tumor cells
- c. Arm A (MCL):
- Phase Ia: Patients with at least one evaluable lesion as defined per RECIST v1.1 solid tumor or 2014 Lugano Classification Criteria for lymphoma, respectively
Phase Ib: Patients with at least one measurable lesion as defined per RECIST v1.1 solid tumor or per 2014 Lugano Classification Criteria for lymphoma, respectively. Note: Radiographic tumor assessment should be performed within 28 days prior to the first dose of study treatment. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
- Fertile men and women of childbearing potential must agree to use an effective method of birth control from providing signed consent and for 180 days after the last investigational product administration (refer to Appendix 6). Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 7 days prior to the first dose of the investigational product.
- After the approval from local health authorities is obtained (if applicable), all patients must agree to provide baseline tumor samples at Screening for biomarker analysis. For TNBC patients in Phase Ib Arm C, positive ROR1 expression as determined by a central IHC assay must be obtained at Screening to be eligible for the study.
- a. Baseline tumor samples can be formalin-fixed paraffin-embedded (FFPE) archival specimens or fresh biopsies collected when deemed medically safe by the Investigator
- b. Acceptable tumor tissue includes core needle punctured, resected or incisional biopsy, or surgical sample. Tissue from tumor progressing at a site of prior radiation may be allowed.
- Fresh biopsy, if applicable, should not be obtained from RECIST, or 2014 Lugano Classification Criteria defined target lesions if possible. Consult the Sponsor for eligibility when no other lesions are suitable for biopsy.
- Has disease that is suitable for local treatment administered with curative intent
- For lymphoma, candidacy for hematopoietic stem cell transplantation (HSCT) based on the Investigator’s judgment
- Has a history of a second malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
- Known central nervous system (CNS) lymphoma or solid tumor CNS metastasis that is either symptomatic, untreated, or requires therapy. Central nervous system metastases that have been treated by complete resection and/or radiotherapy demonstrating stability or improvement are not an exclusion criterion provided they are stable as shown by imaging for at least 4 weeks before Screening without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.
- Other acute or chronic medical or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Has a diagnosis of immunodeficiency, or has an active autoimmune disease or other conditions that require systemic steroid therapy
For solid tumor: > 10 mg daily prednisone equivalents within 14 days prior to the administration of the first dose of CS5001
For lymphoma: > 20 mg daily prednisone equivalents within 28 days prior to the administration of the first dose of CS5001
The use of short-course systemic corticosteroids (≤ 7 days) is permitted, with a wash-out period of 1 week prior to the administration of the first dose of CS5001
- Peripheral edema, pericardial effusion, or ascites indicated for medical intervention limiting activity of daily life. Or with a known history of peripheral vasculopathies including, but not limited to, macro- and micro-angiopathies secondary to diabetes, peripheral arteriopathy of any cause, intermittent claudication, repeated and/or non-healing ulcers of any cause.
- History of Steven’s Johnson’s syndrome or toxic epidermal necrolysis syndrome
- Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, or current ILD/pneumonitis, or suspected ILD/pneumonitis (e.g., idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, etc.)
- Patients with any active infections requiring systemic therapy within 2 weeks prior to the administration of the first dose of the study drug
- Patients known to be human immunodeficiency virus (HIV)-positive or have acquired immune deficiency syndrome (AIDS)
- Patients who are Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C virus (HCV) antibody positive at screening, must not be enrolled until further definite testing with Hepatitis B virus (HBV) DNA titers and HCV RNA tests can conclusively rule out presence of HBV or HCV infection with HBV DNA ≥ 500 for non-HCC, or 2000 IU/mL for HCC or HCV RNA exceeding the lower detection limit, respectively
- Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class III-IV within 6 months prior to the first dose of study drug, or documented a Fridericia’s corrected QT interval (QTcF) of > 470 msec based on the mean value of the triplicate screening ECG
- For Phase Ib: Participation in other studies involving therapies targeting ROR1 prior to study entry and/or during study participation
- Patient who has received major surgery, chemotherapy, definitive radiotherapy, target therapy, immunotherapy, or other anti-cancer therapy within 21 days prior to the administration of the first dose of the study drug, except that chronic luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy is allowed to be continued during the study. Patients who have palliative radiotherapy within 14 days prior to the study treatment or have used a radioactive drug (Strontium, Samarium, etc.) within 56 days prior to the study treatment.
- Administration of a live vaccine within 28 days prior to the administration of the first dose of the study drug
- Patient who has active graft versus host disease. For lymphoma, patients who have received allogeneic stem cell transplantation within 6 months, autologous hematopoietic stem cell transplantation within 100 days, or CAR-T cell therapy within 3 months prior to the administration of the first dose of the study drug.
- Patient who has used antitumor Chinese herbal preparations or Chinese patent medicine within 14 days prior to the administration of the first dose of the study drug
- Patient who has used any other investigational drugs within 21 days prior to the administration of the first dose of the study drug
- History of hypersensitivity or idiosyncrasy to the excipients of the study drug or to any monoclonal antibody
- Any toxic effects of prior therapy or surgical procedures unresolved to baseline severity or NCI-CTCAE Version 5.0 Grade ≤ 1 (except Grade ≤ 2 alopecia, endocrinopathy managed with hormone replacement, sensory neuropathy, or other toxicities not considered a safety risk for the subject at Investigator’s discretion)
- Patients with known active alcohol or drug abuse
- Women who are pregnant or breastfeeding
- Dallas, TX - Mary Crowley Cancer Research - Medical City