A Phase Ib/II, Open Label Study of Siremadlin Monotherapy and in Combination With Donor Lymphocyte Infusion as a Treatment for Patients With Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplantation Who Are in Complete Remission But at High Risk for Relapse.

The purpose of this study was to confirm a safe dose and schedule as well as the preliminary efficacy of siremadlin alone, and in combination with donor lymphocyte infusion (DLI), in adult participants with AML who are in remission following allogeneic stem cell transplantation (allo-SCT) but are at high risk for relapse based on the presence of pre-transplant risk factors.

Start Date23 Feb 2023

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT05599932 / CompletedPhase 1

A Phase 1, Open-label, Multi-center, Single-dose, Parallel Group Study to Evaluate the Pharmacokinetics of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment Compared to Matched Healthy Control Participants

The main purpose of this study is to evaluate the effect of varying degrees of impaired hepatic function (by Child Pugh classification) on the plasma PK of siremadlin after a single oral dose. In addition, safety and tolerability of siremadlin after a single oral dose will be evaluated. The results of this study will inform the decision whether a dose adjustment may be recommended when treating patients with various degrees of impaired hepatic function.

Start Date02 Dec 2022

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT05155709 / TerminatedPhase 1

A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features

A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.
The primary purpose of this study was to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML patients without unacceptable levels of treatment-emergent toxicities.

Start Date17 May 2022

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Siremadlin

100 Translational Medicine associated with Siremadlin

100 Patents (Medical) associated with Siremadlin

Literatures (Medical) associated with Siremadlin

01 Oct 2022·Clinical Lymphoma Myeloma & Leukemia

AML-143 Trial in Progress: Phase Ib/II Study of Siremadlin in Combination With Venetoclax + Azacitidine in Patients With Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy (IC)

Article

Author: Pathak, Dhrubajyoti ; DeAngelo, Daniel J ; Stein, Eytan M ; Xu, Yunnan ; Wei, Andrew H ; Daver, Naval G ; Venditti, Adriano ; Grzesiak, Stephanie

CONTEXT:

Treatments for AML patients unfit for IC are limited. Venetoclax+hypomethylating agents (HMAs) demonstrated improved survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive. Siremadlin is a selective inhibitor of the tumor protein 53 (p53)-murine double minute-2 (MDM2) interaction. AML patients treated with siremadlin experienced a tolerable safety profile and preliminary antitumor activity in a Phase I study (NCT02143635). Initial results from a Phase lb study exploring siremadlin+venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (NCT03940352).

OBJECTIVE:

To describe the study design of a Phase lb/II study assessing the safety and efficacy of siremadlin+venetoclax+azacitidine in AML patients unfit for IC (NCT05155709).

DESIGN:

The study will consist of a safety run-in (part 1) and an expansion phase (part 2).

PATIENTS:

Adult AML patients unfit for IC due to age (≥75 years) or comorbidities are eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated: patients with prior suboptimal response (no CR, CRh, CRi, or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax+azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk features that confer a low likelihood of response to venetoclax+HMAs (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2).

INTERVENTIONS:

Safety run-in/part 1: siremadlin 20 or 30 mg from Day (D)1 to D5 in each 28-day cycle with venetoclax+azacitidine. Arm 1: patients will continue receiving their tolerated venetoclax+azacitidine doses prior to study enrollment. Arm 2: venetoclax will be increased over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m²) from D1-D7 or from D1-D5, and D8+D9. Upon confirmation of the recommended dose for expansion (RDE) for each arm, enrollment for the expansion phase/part 2 will open; patients will be treated with siremadlin at the RDE in combination with venetoclax+azacitidine.

MAIN OUTCOME MEASURES:

Primary endpoints: incidence of dose-limiting toxicities (Arms 1 and 2 separately) and CR rate (Arm 1). Secondary endpoints: safety and tolerability; CR rate (Arm 2); CR/CRh and CR/CRi rates, duration of CR, CRi, and CRh; OS; early mortality; MRD; pharmacokinetics.

01 Oct 2022·Clinical Lymphoma Myeloma & Leukemia

AML-142 Patients at High Risk of Relapse Post-Transplant: A Phase 1 Study Design With a Novel Treatment Strategy Using the Estimand Framework

Article

Author: Xu, Yunnan ; Weber, Hans-Jochen ; Zeiser, Robert ; Widmer, Lukas ; Schmid, Christoph ; Al-Atrash, Gheath ; Weber, Sebastian ; Craddock, Charles ; Eldjerou, Lamis

CONTEXT:

The risk of disease relapse in patients allografted for acute myeloid leukemia (AML) is high and remains the main cause of transplant failure. A potent graft-versus-leukemia (GvL) effect is exerted post-stem cell transplantation (SCT); strategies that may augment a GvL effect have the potential to reduce relapse risk post SCT. Siremadlin/HDM201 is a novel investigational MDM2 inhibitor with single-agent (SA) anti-AML activity. MDM2 inhibitors possess potent immunomodulatory effects (IME) in murine solid tumor and AML models. The post-allogeneic SCT setting is ideal for investigating IME of MDM2 inhibition on the GvL effect.

OBJECTIVE:

To present a study design assessing the safety and preliminary efficacy of treatment with monotherapy siremadlin and in combination with donor lymphocyte infusions (DLIs) for AML post SCT using the estimand framework (ICH E9 [R1] addendum).

DESIGN:

Phase Ib/II proof-of-concept.

PATIENTS:

AML patients in CR post SCT at high risk for relapse based on pre-SCT risk factors.

INTERVENTIONS:

The estimand framework mandates definition of experimental intervention according to the clinical question. Due to the risk of GvHD with DLI early post SCT, siremadlin will first be given to eligible patients as priming monotherapy to prevent early relapse; patients who tolerate siremadlin with no evidence of GvHD are eligible to start siremadlin/DLI. Post combination, patients may continue maintenance SA siremadlin, which intends to prolong/enhance the GvL reaction to eradicate residual leukemic blasts. According to their treatment journey, patients may receive only part of the intervention's sequence (e.g., siremadlin priming monotherapy patients not eligible for DLI combination will continue priming).

MAIN OUTCOME MEASURES:

To determine 1) the siremadlin recommended dose (RD) across all parts of the treatment strategy and 2) preliminary efficacy regardless of the treatment parts received. Siremadlin RD will be determined using a Bayesian logistic regression model to guide dose finding of siremadlin during priming/Cycle 1 and a Bayesian time-to-DLT model to assess the siremadlin combination dose. Efficacy will be assessed by the proportion of patients remaining in CR ≥6 months.

SUMMARY:

The estimand framework guided the design of an AML clinical study post SCT to conceptualize the assessment of safety and efficacy of the treatment strategy, accounting for different patient journeys.

15 Mar 2022·Clinical cancer research : an official journal of the American Association for Cancer ResearchQ1 · MEDICINE

Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

Q1 · MEDICINE

Article

Author: Halilovic, Ensar ; Lin, Chia-Chi ; Jullion, Astrid ; Orlando, Elena J. ; Bauer, Sebastian ; Blay, Jean-Yves ; Clementi, Giorgia ; Cubedo, Ricardo ; Fabre, Claire ; Quek, Richard ; Italiano, Antoine ; Sand Dejmek, Janna ; Guerreiro, Nelson ; Suarez, Cristina ; Hütter-Krönke, Marie Luise ; Abdul Razak, Albiruni R. ; Ferretti, Stephane

Abstract:

Purpose::

Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53–MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.

Patients and Methods::

In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.

Results::

As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1–174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.

Conclusions::

Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.

News (Medical) associated with Siremadlin

18 Sep 2023

·www.pharmaceutical-technology.com

FDA approves GSK’s Ojjaara for treating myelofibrosis patients with anaemia

Phalguni Deswal @Phalguni_GD Ojjaara was included in GSK’s portfolio after the acquisition of Sierra in 2022. Image Credit: William Barton / Shutterstock. The US Food and Drug Administration (FDA) has approved GSK ’s Ojjaara (momelotinib) for treating intermediate or high-risk myelofibrosis patients with anaemia. The intermediate or high-risk myelofibrosis patients include individuals with primary or secondary myelofibrosis (post-polycythaemia vera and post-essential thrombocythemia). In June, the FDA pushed the Prescription Drug User Fee Act (PDUFA) target action date for the drug to September without disclosing any reason for the extension. Recommended Reports Reports LOA and PTSR Model - Ranibizumab Biosimilar in Diabetic Macular Edema GlobalData Reports LOA and PTSR Model - Siremadlin Succinate in Myelofibrosis GlobalData View all Companies Intelligence Novartis AG GSK plc Incyte Corp Sierra Oncology Inc Lancet View all Ojjaara is a once-daily Janus kinase (JAK)1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor initially developed by Sierra Oncology . Ojjaara was included in GSK’s portfolio after the acquisition of Sierra in 2022 . Myelofibrosis is a rare blood cancer that is characterised by the build-up of scar tissue (fibrosis) in the bone marrow. Due to marrow fibrosis, the common symptom of the disease is low blood counts including red blood cells (anaemia). According to the National Organization for Rare Diseases , primary myelofibrosis affects 1.5 people per every 100,000 individuals in the US. The commonly prescribed FDA-approved treatment for myelofibrosis includes Novartis and Incyte ’s Jakafi (ruxolitinib). Jakafi generated $1.2bn in global sales in H1 2023, as per Incyte’s Q2 financial report . GlobalData forecasts Ojjaara to have modest sales of $499m in 2029 compared to Jakafi’s sales of $3.1bn in the same period. GlobalData is the parent company of Pharmaceutical Technology . The approval is based on the two Phase III studies, Momentum (NCT04173494) and Simplify-1 (NCT01969838) which compared Ojjaara to other myelofibrosis therapies, danazol and Jakafi , respectively. The results from the Momentum trial were published in the Lancet and showed a 50% or more reduction in the total symptom score with Ojjaara compared to danazol. Data from the subgroup of patients from the Simplify-1 trial was also part of the approval and showed that Ojjaara reduced the spleen volume response by 35% or more. The commonly observed adverse events included thrombocytopenia (low platelet count), haemorrhage, bacterial infection, fatigue, dizziness, diarrhoea, and nausea. Ojjaara is also being evaluated in other conditions such as non-small cell lung cancer, polycythaemia vera, and pancreatic ductal adenocarcinoma.

Drug ApprovalClinical ResultPhase 3AcquisitionAccelerated Approval

05 Sep 2023

·www.pharmaceutical-technology.com

Chinese NMPA approves AstraZeneca’s Calquence for leukaemia

AstraZeneca is currently analysing Calquence to treat various multiple B-cell blood cancers. Credit: Jonathan Weiss/Shutterstock.com. The Chinese National Medical Products Administration (NMPA) has granted approval for AstraZeneca ’s Calquence (acalabrutinib) to treat chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) in adults. A selective inhibitor of Bruton’s tyrosine kinase (BTK), Calquence is indicated for use in CLL or SLL patients who have received a minimum of one treatment previously. Recommended Reports Reports LOA and PTSR Model - Siremadlin Succinate in Well Differentiated Liposarcoma GlobalData Reports LOA and PTSR Model - Ribociclib Succinate in Well Differentiated Liposarcoma GlobalData View all Companies Intelligence AstraZeneca Plc Ascend GmbH View all The approval was based on positive data from two clinical trials; namely, the Phase III ASCEND trial of Calquence in relapsed or refractory (R/R) CLL patients and a Phase I/II trial in R/R CLL patients in China. According to the data from the Phase I/II trial, treatment with Calquence offered an overall response rate of 83.3% in study subjects. ASCEND findings showed that 88% of trial subjects were alive and free from disease progression after 12 months following treatment with Calquence. AstraZeneca oncology business unit executive vice-president Dave Fredrickson said: “The approval is another step towards our goal of making Calquence available to as many patients as possible and offering physicians a treatment option with a well-established efficacy and tolerability profile. “Patients with chronic lymphocytic leukaemia are often older and dealing with significant comorbidities, and tolerability is a critical factor in their treatment.” Calquence is currently available for treating CLL and SLL in the US and Japan while it is indicated for CLL in the R/R and treatment-naïve patients in the EU and other countries globally. Apart from CLL, the product is also being analysed by the company to treat multiple B-cell blood cancers; namely, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia and marginal zone lymphoma, among others. In March 2023, the Chinese regulator granted conditional approval for Calquence for the treatment of MCL in adults who have received a minimum of one earlier therapy.

Drug ApprovalPhase 3Clinical Result

21 Aug 2023

·www.pharmaceutical-technology.com

Regeneron’s Veopoz scores FDA approval for rare immune disease

Phalguni Deswal @Phalguni_GD Veopoz’s approval was based on the data from the open-label Phase II/III trial (NCT04209634) consisting of ten participants. Image Credit: lev radin / Shutterstock. Regeneron Pharmaceuticals has received US Food and Drug Administration (FDA) approvals for two of its drugs, namely Veopoz (pozelimab-bbfg) and high-dose Eylea (aflibercept) in the last few days. Veopoz is the first drug which has been approved by the FDA for CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy or CHAPLE disease in patients aged one year and older. Recommended Reports Reports LOA and PTSR Model - Siremadlin Succinate in Myelodysplastic Syndrome GlobalData Reports LOA and PTSR Model - Docetaxel Albumin Bound in Fallopian Tube Cancer GlobalData View all Companies Intelligence Bayer AG Regeneron Pharmaceuticals Inc Alnylam Pharmaceuticals Inc Regeneron GmbH View all CHAPLE is a genetic immune disease caused by mutations in the CD55 gene causing overactivation of the complement system. This results in impaired inflammatory response and causes symptoms such as abdominal pain, recurrent infections, oedema, and diarrhoea. Veopoz , a monoclonal antibody, targets and inhibits the protein involved in the activation of the complement system, the C5 complement factor. Additionally, Eylea HD, which is being codeveloped by Regeneron and Bayer , was granted approval to treat ophthalmologic disorders such as wet age-related macular degeneration (wAMD), diabetic retinopathy (DR) and diabetic macular oedema (DME). Veopoz’s approval was based on the data from the open-label Phase II/III trial (NCT04209634) consisting of 10 participants, who all achieved the primary outcome of normalised serum albumin at 12 weeks, with the patients maintaining these levels over 72 weeks of treatment. At 48 weeks, only one patient required an albumin transfusion, compared to the period of 48 weeks before starting treatment, when five patients required a total of 60 transfusions. Additionally, two patients were hospitalised for seven days in 48 weeks after starting treatment, compared to nine patients requiring hospitalisation for a cumulative 268 days in the period before starting treatment. Veopoz is administered through a 30mg/kg intravenous loading dose, followed by weekly weight-based subcutaneous doses. The most commonly observed adverse events were upper respiratory tract infection, fracture, urticaria (itchy rash), and hair loss. Approved therapies for rare diseases have increased in numbers in recent years, with GlobalData forecasting at least 35 US FDA approval in the rare disease areas in 2023. GlobalData is the parent company of Pharmaceutical Technology . Veopoz is also being investigated in other complement system-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH) and myasthenia gravis. The combination therapy of Veopoz and Alnylam Pharmaceuticals’ cemdisiran, a small interfering RNAi C5 inhibitor , is being investigated in an open-label Phase II trial (NCT04888507).

Drug ApprovalClinical ResultPhase 2Immunotherapy

100 Deals associated with Siremadlin

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	DE	Novartis Pharmaceuticals Corp.	23 Feb 2023
Acute Myeloid Leukemia	Phase 2	IT	Novartis Pharmaceuticals Corp.	23 Feb 2023
Acute Myeloid Leukemia	Phase 2	ES	Novartis Pharmaceuticals Corp.	23 Feb 2023
Hematopoietic stem cell transplantation	Phase 2	DE	Novartis Pharmaceuticals Corp.	23 Feb 2023
Hematopoietic stem cell transplantation	Phase 2	IT	Novartis Pharmaceuticals Corp.	23 Feb 2023
Hematopoietic stem cell transplantation	Phase 2	ES	Novartis Pharmaceuticals Corp.	23 Feb 2023
Locally Advanced Soft Tissue Sarcoma	Phase 2	FR	Novartis AG	15 Apr 2022
Metastatic Soft Tissue Sarcoma	Phase 2	FR	Novartis AG	15 Apr 2022
Refractory acute myeloid leukemia	Phase 2	-	Novartis Pharmaceuticals Corp.	15 Nov 2019
Post-polycythemia vera myelofibrosis	Phase 2	AU	China Novartis Institutes for BioMedical Research Co., Ltd.	26 Sep 2019

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04097821 (Adore, ASH 12022 \| ASH 22022) Manual	Phase 1/2	Primary Myelofibrosis	23	Ruxolitinib+Siremadlin (SIR 20mg)	iubqvpcskm(afinlvmytd) = nnzhskufwx yqahpeovzc (lrdgogfclh ) View more	Positive	15 Nov 2022
				Ruxolitinib+Siremadlin (SIR 30mg)	iubqvpcskm(afinlvmytd) = dwromghrjd yqahpeovzc (lrdgogfclh ) View more
NCT03940352 (ASH 12021 \| ASH 22021) Manual	Phase 1	Acute Myeloid Leukemia \| High Risk Myelodysplastic Syndrome	-	Venetoclax+Siremadlin	addflizyyk(wibjafxysk) = lklkbekowx emsyptpchq (jogiulfmbp ) View more	Positive	05 Nov 2021
AACR2017	Phase 1	Advanced cancer	85	Regimen 1A	olrnsdpgxh(qdgwivaelm) = 12%; 0%; 20%; 16% ibzfmeqvtr (isovqlfgsm ) View more	Positive	01 Jul 2017
				Regimen 1B
AACR2017	Phase 1	acute leukemia	37	NVP-HDM201	cxqszqgxke(drqbuuovxr) = n=1 iojdxpvcdh (ngogmzwacr ) View more	-	01 Jul 2017

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