IRB Study Number 20-138
Status Recruiting
Phase Phase 1
Institute Taussig Cancer Institute
Description
Primary Objectives
• Evaluate the safety and tolerability of SEA-CD70
• Identify the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70
Secondary Objectives
• Assess the pharmacokinetics (PK) of SEA-CD70
• Assess the immunogenicity of SEA-CD70
• Assess the antitumor activity of SEA-CD70
Exploratory Objectives
• Assess biomarkers of biological activity, resistance, and predictive biomarkers of response
• Assess SEA-CD70 pharmacokinetic/pharmacodynamic relationships of interest
Inclusion Criteria
SEA-CD70 dose-escalation cohort in relapsed/refractory (HMA-failure) MDS, Part A:
- Subjects with cytologically/histologically confirmed MDS according to the World Health Organization (WHO) classification with the following:
● 5%-20% bone marrow blasts.
● MDS that is relapsed or refractory and must not have other therapeutic options known to provide clinical benefit in MDS available.
● Treatment failure after prior HMA therapy for MDS, defined as one of the following:
○ Progression (per 2006 IWG criteria) at any time after initiation of HMA therapy.
○ Lack of response (failure to achieve CR, PR, or hematologic improvement [HI] per 2006 IWG criteria) after at least 6 cycles of azacitidine or 4 cycles of decitabine.
○ Relapse after achievement of CR, PR, or HI (per 2006 IWG criteria).
○ Intolerance of HMA (Grade 3 or higher non-hematologic toxicity leading to treatment discontinuation).
○ Subjects with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA.
Must be off all treatments for MDS (including HMAs) for ≥4 weeks; growth factors (e.g., G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated.
Age ≥18 years.
Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0–1 (APPENDIX D).
SEA-CD70 expansion cohort in relapsed/refractory (HMA-failure) MDS, Part B:
- Subjects with cytologically/histologically confirmed MDS according to the WHO classification with the following:
● 5%–20% bone marrow blasts.
● MDS that is relapsed or refractory and must not have other therapeutic options known to provide clinical benefit in MDS available.
● Treatment failure after prior HMA therapy for MDS defined as one of the following:
● Progression (per 2006 IWG criteria) at any time after initiation of HMA therapy.
● Lack of response (failure to achieve CR, PR, or HI per 2006 IWG criteria) after at least 6 cycles of azacitidine or 4 cycles of decitabine.
● Relapse after achievement of CR, PR, or HI (per 2006 IWG criteria).
● Intolerance of HMA (Grade 3 or higher non-hematologic toxicity leading to treatment discontinuation).
● Subjects with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA.
Must be off all treatments for MDS (including HMAs) for ≥4 weeks; growth factors (e.g., G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated.
At least one cytopenia (ANC <1800/μL or platelet count <100,000/μL or hemoglobin [Hgb] <10 g/dL).
Age ≥18 years.
ECOG Performance Status of 0–2 (APPENDIX D).
SEA-CD70 expansion cohort in relapsed/refractory AML, Part C:
- Subjects with relapsed/refractory AML according to the WHO 2016 classification (Arber 2016)(except for acute promyelocytic leukemia [APL]):
● Who have received either 2 or 3 previous regimens to treat active disease. Post-remission treatments, intrathecal chemotherapy, and radiotherapy are not considered previous regimens.
● Who have received 1 previous regimen to treat active disease and have at least one of the following:
○ Age >60 and ≤75 years.
○ Primary resistant AML (defined as failure to achieve CR after 1–2 courses of induction therapy).
○ First CR duration <6 months.
○ Adverse-risk per European Leukemia Net (ELN) genetic risk stratification (APPENDIX I) (Dohner 2017)
○ Secondary AML (prior history of MDS or therapy-related).
Age 18-75 years.
ECOG Performance status of 0-2 (APPENDIX D).
All Subjects
- The following baseline laboratory data:
a. WBC count <20,000/μL; use of hydroxyurea to control WBC is acceptable.
b. Serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with Gilbert’s disease, or direct bilirubin ≤2 x ULN if total bilirubin is abnormal.
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN.
d. Estimated glomerular filtration rate (GFR) >60 mL/min using the Modification of Diet in Renal Disease (MDRD) study equation as applicable.
- Subjects of childbearing potential, under the following conditions:
a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 3 days prior to the first dose of SEA-CD70. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation.
b. Must agree not to try to become pregnant during the study and for at least 2 months after the final dose of study drug.
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 2 months after the final dose of study drug.
a. If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at time of informed consent and continuing throughout the study and for at least 2 months after the final dose of study drug (APPENDIX E).
- Subjects who can father children, under the following conditions:
a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study.
b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at time of informed consent and continuing throughout the study.
c. If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options starting at time of informed consent and continuing throughout the study (APPENDIX E).
- The subjects must provide written informed consent.
Exclusion Criteria
History of another malignancy within 3 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
Previous exposure to CD70-targeted agents.
Prior allogeneic hematopoietic stem cell transplant, for any condition.
Central nervous system leukemia based on imaging or documented positive cytology in cerebral spinal fluid.
Any uncontrolled Grade 3 or higher (per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI CTCAE], version 5.0) viral, bacterial, or fungal infection within 14 days prior to the first dose of study treatment. Antimicrobial prophylaxis or ongoing treatment of resolving/controlled infection is permitted.
Subjects who have experienced major surgery (defined as requiring general anesthesia and hospitalization for >24 hours) or significant traumatic injury that would place the subject at undue risk from study procedures, in the opinion of the investigator, within 14 days before the first dose of study treatment. Subjects must have recovered adequately from the surgery/injury, or complications thereof, prior to starting treatment.
Positive for hepatitis B by surface antigen expression. Active hepatitis C infection (positive by PCR or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
Known to be positive for human immunodeficiency virus (HIV).
Known active or latent tuberculosis.
History of clinically significant sickle cell anemia, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura.
History of clinically significant chronic liver disease (e.g., liver cirrhosis) and/or ongoing alcohol abuse.
Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV (APPENDIX F) within 6 months prior to their first dose of SEA-CD70.
Chemotherapy, systemic radiotherapy, biologics, other anti-neoplastic or investigational agents, and/or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of SEA-CD70. Focal radiotherapy that is not completed 2 weeks prior to the first dose of SEA-CD70. Hydroxyurea or 6-mercaptopurine used for cytoreduction may be given up to 24 hours prior to treatment.
Subjects with either of the following:
a. A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 2 weeks of first dose of SEA-CD70 (inhaled, topical, intraocular, intranasal, and intraarticular steroids are permitted in the absence of active immune disease, and steroid premedication for prevention of hypersensitivity reactions to radiographic contrast is permitted).
b. Active known or suspected clinically significant autoimmune disease or clinically significant autoimmune-related toxicity from prior immune-oncology–based therapy (exceptions include vitiligo, controlled type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, and conditions not expected to recur in the absence of an external trigger).
Subjects who are breastfeeding, pregnant, or planning to become pregnant from time of informed consent until 2 months after final dose of study drug.
Known hypersensitivity to any excipient contained in the drug formulation of SEA-CD70.
Estimated life expectancy <12 weeks.
Other serious underlying medical condition that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment and follow-up.
