A Safety Study of SEA-CD70 in Patients With Myeloid Malignancies

Study Overview
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Brief Summary
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This trial will look at a drug called SEA-CD70 with and without azacitidine, to find out if it is safe for patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It will study SEA-CD70 to find out what its side effects are and if it works for AML and MDS. A side effect is anything the drug does besides treating cancer. This study will have six groups or parts. Part A will find out how much SEA-CD70 should be given to patients. Part B will use the dose found in Part A to find out how safe SEA-CD70 is and if it works to treat patients with MDS. Part C will use the dose found in Part A to find out how safe SEA-CD70 is and if it works to treat patients with AML. Part D will find out how much SEA-CD70 with azacitidine should be given to patients. Part E will use the dose found in Part D to find out how safe SEA-CD70 with azacitidine is and if it works to treat patients with MDS that has not been treated. Part F will use the dose found in Part D to find out how safe SEA-CD70 with azacitidine is and if it works to treat patients with MDS or AML.

Detailed Description
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This is a phase 1, open-label, multicenter, dose-finding, and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SEA-CD70 monotherapy and SEA-CD70 in combination with azacitidine in adults with myeloid malignancies. The study will be conducted in up to 6 parts. Part A is a dose-escalation cohort designed to identify the MTD or recommended expansion dose of SEA-CD70 monotherapy in participants with relapsed/refractory (hypomethylating agent [HMA]-failure) MDS. Part B is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 monotherapy in participants with relapsed/refractory (HMA-failure) MDS. Part C is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 monotherapy in participants with relapsed/refractory AML. Part D contains dose-finding/dose optimization cohorts designed to evaluate the safety/tolerability and identify the recommended expansion dose of SEA-CD70 in combination with azacitidine in participants with 1) relapsed/refractory (HMA-failure) MDS or AML arising from MDS, and 2) previously untreated higher-risk (IPSS intermediate-2 or high risk) MDS. Part E is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 in combination with azacitidine in participants with previously untreated higher-risk (IPSS intermediate-2 or high risk) MDS. Part F is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 in combination with azacitidine in participants with relapsed/refractory (HMA-failure) MDS or AML arising from MDS.

Official Title
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A Phase 1 Study of SEA-CD70 in Myeloid Malignancies

Conditions
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Myelodyspastic Syndrome, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: SEA-CD70
* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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Part A Inclusion Criteria Participants with cytologically/histologically confirmed MDS according to the 2016 World Health Organization (WHO) classification with the following: Measurable disease per WHO MDS with excess blasts criteria as defined either: 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood or 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood 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 hypomethylating agent (HMA) therapy for MDS, defined as one of the following: Progression (per 2006 International Working Group [IWG] criteria) at any time after initiation of HMA therapy. Lack of response (failure to achieve complete remission [CR], partial response [PR], or hematologic improvement [HI] per 2006 IWG criteria) after at least 6 cycles of azacitidine (or equivalent HMA) or 4 cycles of decitabine (or equivalent HMA). 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). Participants with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA. Must be off HMA therapy ≥ 2 weeks and must be off any other treatments for MDS for ≥ 4 weeks prior to first dose of SEA-CD70; growth factors and transfusions are allowed before and during the study as clinically indicated Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Part B Inclusion Criteria Participants with cytologically/histologically confirmed MDS according to the WHO classification with the following: Measurable disease per WHO MDS with excess blasts (MDS-EB) criteria as defined either: 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood, or 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood 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). Participants with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA. Must be off HMA therapy ≥ 2 weeks and must be off any other systemic treatments for MDS for ≥ 4 weeks prior to first dose of SEA-CD70; growth factors and transfusions are allowed before and during the study as clinically indicated. ECOG Performance Status of 0-2 Part C Inclusion Criteria Participants with relapsed or refractory AML according to the WHO 2016 classification (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 Secondary AML (prior history of MDS or therapy-related) Age 18-75 years ECOG performance status of 0-2 Parts D and F Inclusion Criteria Participants with one of the following confirmed diagnoses: MDS with excess blasts (MDS-EB), defined as either: 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood (MDS-EB-1), or 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood (MDS-EB-2) AML with ≤ (less than or equal to) 30% blasts in the peripheral blood or bone marrow, with known history of MDS Disease which has relapsed, failed to respond after minimum of 6 cycles, or progressed following an HMA in the immediately preceding line of therapy. Eligible for continued therapy with azacitidine Must be off any other systemic treatment for AML/MDS. Must be off HMA therapy ≥ (greater than or equal to) 2 weeks and any other systemic treatments for MDS for ≥ (greater than or equal to) 4 weeks prior to first dose of SEA-CD70 ECOG Performance Status 0-2 Parts D and E Inclusion Criteria Participants with previously untreated, cytologically/histologically confirmed MDS according to WHO classification with the following: Measurable disease per WHO MDS with excess blasts (MDS-EB) criteria as defined either: 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood (MDS-EB-1), or 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood (MDS-EB-2) Participants with higher-risk MDS per International Prognostic Scoring System (IPSS) ECOG Performance Status 0-2 Exclusion Criteria (All Parts) 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. 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 History of clinically significant sickle cell anemia, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura Parts D and F only: Prior oral HMA or oral HMA-combinations

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Parts B and C may enroll in parallel after enrollment of Part A is complete. Part D will enroll after Part A is complete. Parts E and F will enroll in parallel once Part D is complete.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>SEA-CD70 dose escalation cohort in relapsed/refractory (HMA-failure) MDS | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>|
| Experimental: Part B<br>SEA-CD70 expansion cohort in relapsed/refractory (HMA-failure) MDS | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>|
| Experimental: Part C<br>SEA-CD70 expansion cohort in relapsed/refractory AML | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>|
| Experimental: Part D<br>SEA-CD70 + azacitidine dose-finding/dose optimization cohorts in relapsed/refractory MDS or AML arising from MDS, and previously untreated higher-risk MDS | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>Drug: azacitidine<br>* 75mg/m^2 injected under the skin (SC; subcutaneous) or given into the vein (IV; intravenously) on Days 1 through 7 of each treatment cycle.<br>* Other names: VIDAZA;|
| Experimental: Part E<br>SEA-CD70 + azacitidine expansion cohort in previously untreated higher-risk MDS | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>Drug: azacitidine<br>* 75mg/m^2 injected under the skin (SC; subcutaneous) or given into the vein (IV; intravenously) on Days 1 through 7 of each treatment cycle.<br>* Other names: VIDAZA;|
| Experimental: Part F<br>SEA-CD70 + azacitidine expansion cohort in relapsed/refractory MDS or AML arising from MDS | Drug: SEA-CD70<br>* Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle<br>Drug: azacitidine<br>* 75mg/m^2 injected under the skin (SC; subcutaneous) or given into the vein (IV; intravenously) on Days 1 through 7 of each treatment cycle.<br>* Other names: VIDAZA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Number of participants with laboratory abnormalities | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Number of participants with a dose-limiting toxicity (DLT) at each dose level (Parts A and D only) | To be summarized using descriptive statistics. | Though end of DLT evaluation period; up to approximately 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC - Area under the plasma concentration-time curve | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Tmax - Time to maximum concentration attained | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Cmax - Maximum observed plasma concentration | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Ctrough - Minimum plasma concentration per dosing interval | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| T1/2 - Terminal elimination half-life | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Incidence of antidrug antibodies (ADA) | To be summarized using descriptive statistics. | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | 
| Complete remission (CR) Rate | Proportion of participants with AML or MDS who achieve CR | Up to approximately 4 years | 
| Complete remission with incomplete blood count recovery (CRi) rate | Proportion of participants with AML who achieve CRi | Up to approximately 4 years | 
| Complete remission with partial hematologic recovery (CRh) rate | Proportion of participants with AML or MDS who achieve CRh | Up to approximately 4 years | 
| Hematologic response (HI) rate | Proportion of MDS participants with HI | Up to approximately 4 years | 
| Overall response rate (ORR) | For AML, the proportion of participants who achieve a best response of CR, CRi, CRh, or partial response (PR). For MDS, the proportion of participants who achieve a best response of CR, CRh, or PR. | Up to approximately 4 years | 
| Blast clearance rate for participants with MDS | Proportion of participants with MDS who achieve a best response of CR, CRh, or Marrow CR | Up to approximately 4 years | 
| Duration of remission (DOR) | For AML, the time from first CR, CRi, CRh, or PR to the first documentation of disease progression or death due to any cause. For MDS, the time from first documentation of PR, CR, or CRh to the first documentation of disease progression or death due to any cause. | Up to approximately 4 years | 
| Overall survival (OS) | Time from start of study treatment to the date of death due to any cause | Up to approximately 4 years | 
| Event-free survival (EFS) | Time from first dose to the first documentation of progression, failure to achieve remission within the first 6 cycles, disease relapse, or death due to any cause, whichever comes first. | Up to approximately 4 years | 
| MRD-negative ORR | Proportion of participants with AML or MDS who achieve objective response and MRD-negative status | Up to approximately 4 years | 
| Time to response (TTR) | Time from start of study treatment to the first documentation of objective response | Up to approximately 4 years | 
| Rate of conversion to transfusion independence (TI) | Proportion of participants who convert from transfusion dependence at baseline to TI post-baseline | Up to approximately 4 years | 
| Rate of TI maintenance | Proportion of participants who were TI at baseline and maintain TI post-baseline | Up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seattle Genetics