Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

All Drugs and Chemicals

Clotrimazole

Miconazole

Antifungal Agents

Up to 9 dose levels will be evaluated in subjects not receiving specific azole antifungal treatment.

Up to 9 dose levels will be evaluated in subjects receiving specific azole antifungal treatment.

SGR-2921

Study Physician

Marcello Rotta, MD

Eunice Wang, MD

Hetty Carraway, MD

Alice Mims, MD

Luke Fletcher, MD

Elie Traer, MD

Gina Keiffer, MD

Steven Strickland, MD

Aravind Ramakrishnan, MD

Courtney DiNardo, MD

Daniel Weiss, M.D.

The purpose of this study is to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended dose (RD) of SGR-2921.

This is a study of SGR-2921, an oral, small molecule inhibitor of cell division cycle 7-related protein kinase (CDC7), in subjects with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and/or recommended dose (RD) of SGR-2921.

Exploratory cohorts may evaluate additional PK, PD, preliminary anti-tumor activity, and safety to establish the SGR-2921 RD. A planned amendment will evaluate SGR-2921 in combination with other approved AML/MDS treatments such as hypomethylating agents (HMA), BCL2 inhibitors, IDH inhibitors or FLT3 inhibitors, in patients with AML and/or MDS.

Study of SGR-2921 in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A First-In-Human, Phase 1, Dose Escalation Study of SGR-2921 as Monotherapy In Subjects With Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0.

Uncorrected QT interval, QTcF, PR duration, QRS interval, and RR interval.

Concentrations of SGR-2921 in plasma are measured at various timepoints following its administration to calculate typical exposure/PK parameters, including, but not limited to, the maximal plasma concentration (Cmax).

Concentrations of SGR-2921 in plasma are measured at various timepoints following its administration to calculate typical exposure/PK parameters, including, but not limited to, the minimum plasma concentration (Cmin).

Concentrations of SGR-2921 in plasma are measured at various timepoints following its administration to calculate typical exposure/PK parameters, including, but not limited to, the time to maximal plasma concentration (tmax).

Concentrations of SGR-2921 in plasma are measured at various timepoints following its administration to calculate typical exposure/PK parameters, including, but not limited to, the area under the concentration versus time curve (AUC).

The percentage of subjects with CR, CR with Partial Hematologic Recovery (CRh), and CR with Incomplete Blood Count Recovery (CRi).

The percentage of subjects achieving CR, CRh, CRi, morphologic leukemia-free state (MLFS) and Partial Response (PR).

The percentage of subjects achieving CR and PR.

The time from first response (CR, CRh, CRi, MLFS, or PR) to the date of initial objectively documented progression or death due to any cause, whichever occurs first.

The time from first response (CR or PR) to the date of initial objectively documented progression or death due to any cause, whichever occurs first.

Schrödinger, Inc.

Antineoplastic Agents

Amino Acids

Venetoclax

Gilteritinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Different combinations of dose levels for venetoclax in combination with gilteritinib will be administered to determine the recommended phase 2 dose (RPTD).

Participants will receive venetoclax in combination with gilteritinib at the dose determined in dose escalation portion.

ABBVIE INC.

A dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of venetoclax, in combination with gilteritinib, in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have failed to respond to, and/or have relapsed or progressed after at least 1 prior therapy.

A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia

A Multicenter, Open-Label Phase 1b Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

The RPTD of co-administered venetoclax and gilteritinib will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.

Modified CRc rate is defined as the proportion of participants with documented complete response (CR) + CR with partial blood count recovery (CRp) + CR with incomplete blood count recovery (CRi) plus Morphologic Leukemia-Free State (MLFS) based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).

Maximum observed plasma concentration (Cmax) of study drug.

Time to maximum plasma concentration (Tmax) of study drug.

Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug.

Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug.

CRc is defined as the proportion of participants with documented CR + CRp + CRi based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).

DOR of modified CRc will be defined as time from the first date achieving modified CRc to disease progression (including morphologic relapse) or death from any cause whichever is earlier.

It is defined as the proportion of participants achieving CR or CRh based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).

DOR of CR + CRh will be defined as time from the first date achieving CR and/or CRh to disease progression (including morphologic relapse) or death from any cause whichever is earlier.

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Astellas Pharma Inc

Genentech, Inc.

AbbVie

Group I: Relapsed AML-patients with blast cell reduction to \<20% before the second course of induction therapy. These patients will receive conventional SCT.

Group II: Patients with non response to frontline treatment of AML, patients with blast cells \<20% before the second course of induction therapy who do not achieve a second remission and relapsed AML-patients with blast cells \>=20% before the second course of induction therapy. If these patients have a matched donor (MSD/MD) they will receive SCT with "FLAMSA".

Group III: Patients who are eligible for Group II but have no matched donor. These patients will receive SCT from a haploidentical donor.

\> = 2 x 10\*8 nucleated cells (WBC)/kg body weight of the recipient or rather \> = 4 x 10\*6 nucleated CD34+ cells / kg body weight are required for engraftment. Suspension of stem cells is administered via intravenous infusion.

Hematopoietic stem cells from bone marrow or peripheral blood

Martin Sauer, Prof. Dr.

1. To evaluate whether stem cell transplantation from a matched sibling donor is equivalent to a matched unrelated donor in in a second complete remission of acute myeloid leukemia (AML).
2. To evaluate whether stem cell transplantation (SCT) after chemotherapy (FLAMSA-schema) increases survival compared to a threshold derived from historical data
3. To evaluate whether SCT from haploidentical donors for children having no matched donor will result in better survival with acceptable toxicity.

Target variables:

* Treatment response
* Event Free Survival
* Leukemia Free Survival
* Graft Versus Host Disease
* Regimen related toxicity

Allogenic Stem Cell Transplantation for Children, Adolescents and Young Adults With Relapsed or Refractory AML

Allogenic Stem Cell Transplantation for Children, Adolescents and Young Adults With Relapsed or Refractory AML; Multi Center Therapy Concept

Hannover Medical School

Cytarabine

Melphalan

Clofarabine

Antimetabolites

Induction therapy with clofarabine/cytarabine. Post-remission therapy with either allogeneic HCT after conditioning with clofarabine/melphalan if a donor is available, or clofarabine/cytarabine if no donor is available

Induction and consolidation therapy / conditioning therapy with Clofarabine

Johannes Schetelig, MD

In relapsed or refractory AML allogeneic HCT is considered to be the only treatment by which long-term disease-free survival can be achieved. Despite this favorable prospect, even in younger patients with relapsed AML only about 40% of the patients reach allogeneic HCT. A number of factors contribute to this low rate of transplantation, among them moderate activity of the salvage regimens and accumulating toxicities which prevent from transplantation; Prospective clinical trials in this indication usually focus either on the rate of CR achieved after a defined number of cycles of salvage therapy or on transplantation modalities. The consequent integration of salvage therapy into a transplant strategy accounting for the time-dependent process of donor search has not been studied so far.

The objective of this study is to evaluate the safety and efficacy of clofarabine salvage therapy prior to allogeneic HCT.

All patients are scheduled for at least one cycle of induction therapy with CLARA. CLARA contains clofarabine 40 mg/m2 (1 hr infusion) days 1-5 followed 3 hours after the end of infusion by intermediate dose cytarabine 1 g/m2 (2 hrs infusion) days 1-5. Patients with moderate early response (reduced marrow blast count but ≥10% at day 15) or patients with progressive disease during delayed hematologic recovery (beyond day 42) may receive re-induction therapy similar to the first cycle induction therapy.

Study treatment comprises up to two cycles of induction therapy and one to two cycles of consolidation chemotherapy for patients without a donor. Consolidation therapy is reduced by 25% and consists of clofarabine 40 mg/m2 (1 hr infusion) days 1-4 followed 3 hours after the end of infusion by intermediate dose cytarabine 1 g/m2 (2 hrs infusion) days 1-4.

Patients for whom a donor can be identified may proceed to allogeneic HCT after CLARA I adopting the concept of allogeneic HCT in aplasia. Patients for whom donor search is more time consuming should proceed to allogeneic HCT once a donor has been identified.

Patients who have achieved a response after the last cycle of CLARA will receive clofarabine as part of the conditioning regimen. Clofarabine and melphalan may only be given as conditioning therapy to patients with HLA-compatible donors with a maximum of one mismatch refering to the HLA-loci A, -B, -C and -DRB1. Conditioning therapy then contains clofarabine 30 mg/m2 (1 hr IV infusion) days -6 to -3 and melphalan 140 mg/m2 (1 hour IV infusion) on day -2.

Clofarabine Salvage Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Clofarabine Salvage Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Treatment success is defined as a complete remission (CR, CRi or CRchim) at final response assessment after having completed the study treatment. CR and CRi are defined according to standard criteria (ELN). Complete remission by chimerism (CR chim) is defined as a \>95% overall donor chimerism assessed by STR-PCR in bone marrow and absence of extramedullary disease together with an absolute neutrophil count \>0.5 /nL (500/μL).

Rate of patients who finally proceeded to allogeneic HCT after bridging therapy with Clofarabine

Cause specific analysis of treatment failure

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of SGR-2921 in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT05961839	Acute Myeloid L... High-Risk and V...	SGR-2921	18 Years -	Schrödinger, Inc.
A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia	NCT03625505	Acute Myeloid L...	Venetoclax Gilteritinib	18 Years -	AbbVie
Allogenic Stem Cell Transplantation for Children, Adolescents and Young Adults With Relapsed or Refractory AML	NCT00606723	Acute Myeloid L...	Hematopoietic s...	- 21 Years	Hannover Medical School
A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia	NCT03625505	Acute Myeloid L...	Venetoclax Gilteritinib	18 Years -	AbbVie
Study of SGR-2921 in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT05961839	Acute Myeloid L... High-Risk and V...	SGR-2921	18 Years -	Schrödinger, Inc.
Clofarabine Salvage Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)	NCT01295307	Acute Myeloid L...	Clofarabine	40 Years -	Technische Universität Dresden

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