On June 12, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that three posters relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, JUN 12, 2020, View Source [SID1234561026]). The data in these posters are based on a data cutoff of April 17, 2020, and reflect an analysis of clinical activity in 51 first-line (1L) and 73 second-line (2L) patients.

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"I’m encouraged that the initial signals of activity with CPI-0610, such as spleen and symptom responses, that were presented last December at ASH (Free ASH Whitepaper) continue to be observed in a larger dataset presented in these EHA (Free EHA Whitepaper) posters," said Claire Harrison, D.M. (Oxon.), Professor of Haematology and a MANIFEST investigator. "In addition, we continue to see signals of disease modification, such as increases in hemoglobin, conversions of transfusion-dependent patients to transfusion independence, and bone marrow fibrosis improvements. If corroborated in further testing, these data suggest that CPI-0610 could potentially change the treatment paradigm in MF."

"We are excited about the emerging profile of CPI-0610," said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. "Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases."

Data Highlights

Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients

37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen volume reduction of 51%
19 of 30 evaluable patients (63%) achieved SVR35 at 24 weeks (the primary endpoint for Arm 3) and had a median spleen volume reduction of 53%
17 of 29 evaluable patients (59%) achieved a 50% improvement in Total Symptom Score (TSS50) at 24 weeks and had a median TSS improvement of 64%
No evidence of correlation between SVR35 response and baseline risk status, platelet count, or spleen volume
Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A
5 of 21 (24%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 1B) and 9 of 19 (47%) evaluable non-TD patients achieved TSS50 at 24 weeks
11 of 19 (58%) non-TD patients on treatment for at least 12 weeks without any transfusions achieved a ≥1.5 g/dL mean increase in hemoglobin
Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

11 of 32 (34%) evaluable TD patients converted to TI, the primary endpoint for cohort 2A
4 of 18 (22%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 2B) and 7 of 19 (37%) evaluable non-TD patients achieved TSS50 at 24 weeks
Safety

CPI-0610 in MANIFEST, both as monotherapy and in combination with ruxolitinib and in both JAK-inhibitor-naïve and JAK-inhibitor-experienced and -ineligible patients, was generally well tolerated.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 43 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (14.0%), anemia (9.3%), diarrhea (4.7%), and respiratory tract infection (2.3%). Six patients discontinued treatment because of TEAEs. There were no Grade 4 or Grade 5 TEAEs.

Among the most common TEAEs in 70 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (22.9%), anemia (7.1%), fatigue (5.7%), diarrhea (4.3%), respiratory tract infections (4.3%), nausea (2.9%), and abdominal pain (1.4%). Grade 4 TEAEs included thrombocytopenia (1.4%) and anemia (1.4%). Seven patients discontinued treatment due to TEAEs, including four Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), and disease progression.

Among the most common TEAEs in 64 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (15.6%), respiratory tract infections (3.1%), and thrombocytopenia (1.6%). Grade 4 TEAEs included thrombocytopenia (3.1%), anemia (1.6%), and respiratory tract infection (1.6%). Four patients discontinued treatment due to TEAEs, including two Grade 5 TEAEs, each due to multi-organ failure due to sepsis.

For further details, please see the EHA (Free EHA Whitepaper) poster presentations here.

EHA Poster Presentations

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK Inhibitor Treatment Naive Myelofibrosis Patients: Update of MANIFEST Phase 2 Study (Presentation Code: EP1084)

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, as Monotherapy in Advanced Myelofibrosis Patients Refractory / Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study (Presentation Code: EP1091)

TITLE: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, as "Add-on" to Ruxolitinib (Rux), in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study (Presentation Code: EP1083)

Session: Myeloproliferative Neoplasms—Clinical

Date and Time: June 12, 2020, 8:30 AM CEST/2:30 AM EDT

Investor Event

Constellation will host a virtual analyst/investor event and conference call on June 12 at 8:00 AM EDT to discuss the data from these three posters relating to the MANIFEST clinical trial for CPI-0610 being presented at the European Hematology Association (EHA) (Free EHA Whitepaper) meeting. The agenda of the event will include:

An overview of myelofibrosis (MF) and the potential impact of Constellation’s BET inhibitor CPI-0610 in treating MF
A review of the data from the MANIFEST clinical trial presented in the EHA (Free EHA Whitepaper) posters
A live question-and-answer session
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source To participate in the live question-and-answer session, please dial (877) 473-2077 (domestic) or (661) 378-9662 (international) and refer to conference ID 6275774.

EZH2 Program Prioritization

Constellation reported that it plans to prioritize further clinical development of its next-generation EZH2 inhibitor CPI-0209. The decision is based on a recent data cut and review of ProSTAR, the ongoing Phase 1b/2 clinical study evaluating CPI-1205, a small-molecule inhibitor of EZH2, combined with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). The data did not demonstrate the definitive signal of activity necessary to advance the program into pivotal studies in mCRPC. A full data set from ProSTAR will be presented at a future medical meeting.

"We thank the patients and investigators who participated in ProSTAR," said Jigar Raythatha. "While we are disappointed with the outcome of this study, we remain committed to EZH2 as an important cancer target and will apply the learnings from ProSTAR to our second-generation EZH2 inhibitor, CPI-0209. We believe the deeper and more durable target engagement as well as the improved metabolic properties that CPI-0209 demonstrated in preclinical studies give it the potential to be a best-in-class EZH2 inhibitor for use in a broad range of cancer types. CPI-0209 is progressing through the dose escalation portion of a phase 1/2 clinical trial, and we expect to determine a recommended Phase 2 dose later in the year."

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

About ProSTAR

ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205, a potent and highly selective small-molecule EZH2 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) in the second-line setting. The ProSTAR study is evaluating CPI-1205 in combination with either enzalutamide or abiraterone/prednisone ("abiraterone"), which are androgen receptor signaling (ARS) inhibitors, in mCRPC patients who experienced disease progression while receiving the other ARS inhibitor.

On June 12, 2020 ADC Therapeutics SA (NYSE:ADCT), a clinical-stage oncology-focused biotechnology company leading the development and commercialization of next-generation antibody drug conjugates (ADCs) with highly potent and targeted pyrrolobenzodiazepine (PBD) dimer technology, reported maturing data from LOTIS 2, a pivotal Phase 2 clinical trial of loncastuximab tesirine (Lonca, formerly ADCT-402) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including an overall response rate of 48.3%, a complete response rate of 24.1% and manageable toxicity (Press release, ADC Therapeutics, JUN 12, 2020, View Source [SID1234561061]). The Company also announced interim results from LOTIS 3, a Phase 1/2 clinical trial of Lonca combined with ibrutinib, which highlight the potential of Lonca to advance into earlier lines of therapy in combination with other therapies. The data are being presented in an oral presentation and e-Poster at the virtual 25th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (EHA25).

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"Our two presentations at EHA (Free EHA Whitepaper)25 highlight Lonca’s potential as both a single agent and in combination with other therapies for patients with non-Hodgkin lymphoma," said Jay Feingold, MD, PhD, Senior Vice President and Chief Medical Officer of ADC Therapeutics. "In LOTIS 2, Lonca demonstrated important anti-tumor activity and durability, as well as manageable toxicities, across a broad population of hard-to- treat, relapsed or refractory DLBCL patients, including patients with poor prognosis, those who never responded to prior therapy and those who received prior stem cell transplant."

"We are pleased to be on track to file a Biologics License Application (BLA) with the U.S. Food and Drug Administration for Lonca for the treatment of relapsed or refractory DLBCL in the second half of 2020," said Chris Martin, Chief Executive Officer of ADC Therapeutics. "If approved, we look forward to launching Lonca in mid-2021. We are also planning to initiate LOTIS 5, a post-marketing confirmatory clinical trial of Lonca in combination with rituximab, which we believe will support a supplemental BLA for Lonca to be used as a second-line therapy for the treatment of relapsed or refractory DLBCL."

Oral Presentation of Initial Results of Lonca Pivotal Phase 2 Clinical Trial (Abstract S233)

LOTIS 2, a Phase 2, multi-center, open-label, single-arm clinical trial, is evaluating the efficacy and safety of Lonca in patients with relapsed or refractory DLBCL following ≥2 lines of prior systemic therapy. Patients received 30-minute intravenous infusions of Lonca once every three weeks at a dose of 150 μg/kg for the first two cycles, followed by 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurred first. As of the data cut-off date of April 6, 2020, 145 patients were enrolled and received a mean of 4.3 cycles of Lonca (range: 1-15).

Key data include:

Lonca achieved an overall response rate (ORR) of 48.3% (70/145 patients) and a complete response rate (CRR) of 24.1% (35/145 patients), compared to an ORR of 45.5% (66/145 patients) and CRR of 20.0% (29/145 patients) in the previous data cut (October 14, 2019)
Patients refractory to first-line or last-line prior therapy had ORRs of 37.9% and 36.9%, respectively
The median duration of response has increased to 10.25 months in the more mature data cut, compared to 6.7 months in the previous data cut (October 14, 2019)
Patients had received a median of 3 prior lines of therapy
The toxicity profile was manageable and no new safety concerns were identified
The most common grade ≥3 treatment-emergent adverse events in ≥10% of patients were: neutropenia (25.5%) with low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), GGT increased (16.6%) and anaemia (10.3%)
"Despite recent advances in DLBCL treatment, outcomes for patients with relapsed or refractory disease remain poor," said Carmelo Carlo-Stella, MD, Professor of Hematology, Humanitas University, Section Chief, Lymphoid Malignancies, Humanitas Cancer Center, and an investigator for the trial. "The substantial single-agent anti-tumor activity Lonca has demonstrated in patients with relapsed or refractory DLBCL who failed established therapies underscores the potential of this CD19-targeted, PBD-based ADC to fill a critical unmet need."

e-Poster with Interim Results of Phase 1/2 Clinical Trial of Lonca Combined With Ibrutinib (Abstract EP1284)

LOTIS 3, a Phase 1/2 open-label, single-arm dose escalation and dose expansion clinical trial, is evaluating the safety and efficacy of Lonca in combination with ibrutinib in patients with relapsed or refractory DLBCL or mantle cell lymphoma (MCL). Lonca is administered as 30-minute intravenous infusions using a standard 3+3 dose escalation design at doses of 60 or 90 μg/kg. Patients receive Lonca every three weeks for the first two doses, with concurrent fixed-dose ibrutinib (560 mg/day, oral) for up to one year. As of the data cut-off date of April 6, 2020, 25 patients have been enrolled, including 23 patients with DLBCL and two patients with MCL, and 18 patients were evaluable for antitumor activity. The trial continues to enroll patients.

Key interim data from the Phase 1 portion of the trial include:

Across both Lonca dose levels of 60 and 90 μg/kg, the combination with ibrutinib has demonstrated an ORR of 66.7% and a CRR of 50.0%
At the recommended Phase 2 Lonca dose of 60 μg/kg, the combination with ibrutinib has demonstrated an ORR of 75.0% and CRR of 58.3%
The combination has a manageable toxicity profile
The most common grade ≥3 treatment-emergent adverse events in ≥10% of patients were thrombocytopenia (20%) and anemia (12%)
Patients had received a median of 2 prior lines of therapy
Pharmacokinetic profiles demonstrate good exposure throughout the dosing interval
"As patients with relapsed or refractory DLBCL or MCL have a poor prognosis and limited salvage treatment options, it is important to explore the potential for combinations of drugs with different mechanisms of action to increase clinical activity compared to either agent alone," said Julien Depaus, MD, Department of Hematology, CHU UCL Namur. "Based on synergies demonstrated in preclinical research and the interim results of the Phase 1 portion of this clinical trial, I believe the combination of Lonca and ibrutinib warrants further evaluation as a treatment option for patients with relapsed or refractory DLBCL or MCL."

Conference Call and Webcast

ADC Therapeutics will host a live conference call and webcast today, Friday, June 12, 2020, at 8:30 a.m. EDT, to highlight the data presented at EHA (Free EHA Whitepaper)25. To access the call, please dial 833-526-8381 (domestic) or +41 225 805 976 (international) and request to join the ADC Therapeutics conference call. A live webcast of the presentation will be available on the Investors section of the ADC Therapeutics website at www.adctherapeutics.com.

About Loncastuximab Tesirine (Lonca)

Loncastuximab tesirine (Lonca, formerly ADCT-402) is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Once bound to a CD19-expressing cell, Lonca is designed to be internalized by the cell, following which the warhead is released. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.

Lonca is being evaluated in LOTIS 2, a pivotal Phase 2 clinical trial in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and LOTIS 3, a Phase 1/2 trial in combination with ibrutinib in patients with relapsed or refractory DLBCL or mantle cell lymphoma (MCL).

On June 12, 2020 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported updated data on one of its investigational CD20xCD3 T-cell engaging bispecific antibodies, glofitamab (formerly known as CD20-TCB), in people with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) (Press release, Hoffmann-La Roche, JUN 12, 2020, View Source [SID1234561027]). Updated results from the phase I dose-escalation NP30179 study [NCT03075696] of glofitamab, administered via intravenous infusion for a fixed-duration of up to 12 21-day cycles, showed durable complete responses (CRs) in heavily pre-treated patients who had received a median of three prior lines of therapy. These data feature in an oral presentation (abstract #S241) at the European Hematology Association (EHA) (Free EHA Whitepaper) 25th Annual Congress Virtual Edition, taking place from 11-14 June 2020.

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"Non-Hodgkin lymphomas such as diffuse large B-cell lymphoma may present considerable treatment challenges, especially cases involving multiple relapses," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "We’re encouraged by these early results which support the potential of glofitamab for patients who have failed multiple prior lines of therapy and need new treatment options urgently."

Updated efficacy data from the ≥0.6mg and ≥10mg cohorts showed high response rates across NHL subtypes.

In the ≥0.6mg cohorts, the investigator-assessed CR rate was 30.9% (38/123) for patients with aggressive NHL and the investigator-assessed overall response rate (ORR) was 45.5% (56/123). For patients with indolent NHL, the investigator-assessed CR rate was 52.2% (12/23) and the investigator-assessed ORR was 65.2% (15/23).
In the ≥10mg cohorts, the investigator-assessed CR rate was 34.1% (29/85) for patients with aggressive NHL and the investigator-assessed ORR was 49.4% (42/85). For patients with indolent NHL, the investigator-assessed CR rate was 50.0% (9/18) and the investigator-assessed ORR was 66.7% (12/18).
CRs also appeared durable. Of the patients achieving a CR in the ≥0.6mg cohorts, 72.7% (24/33) with aggressive NHL and 81.8% (9/11) with indolent NHL maintained their CR by the data cut-off date (17 April 2020). Median duration of CR was not reached in either group after a median follow-up of 10.2 months.
The safety profile of glofitamab was consistent with its mechanism of action. Common adverse events (AEs) occurring in over 15% of participants in the ≥0.6mg cohorts (n=156) were cytokine release syndrome (CRS; n=88, 56.4%), neutropenia (n=48, 30.8%), pyrexia (n=47, 30.1%), anaemia (n=35, 22.4%) and thrombocytopenia (n=26, 16.7%). The majority of CRS events were low grade (Grade 1-2), were associated with the first cycle, and were manageable.

A robust clinical development programme for glofitamab is ongoing, investigating the molecule alone and in combination with other Roche and non-Roche molecules. Combination regimens include studies with Polivy (polatuzumab vedotin), Tecentriq (atezolizumab), MabThera/Rituxan (rituximab) and Gazyva/Gazyvaro (obinutuzumab) in NHL and other blood cancers, across a variety of settings and tumour types, including earlier treatment lines, to identify where glofitamab may be able to provide benefit over current treatment options.

About glofitamab
Glofitamab is an investigational CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells. Glofitamab is based on a novel structural format which we call ‘2:1’, which refers to the structure of the antibody. It is engineered to have two ‘Fab’ regions which bind to CD20, and one ‘Fab’ region which binds to CD3. A robust clinical development programme for glofitamab is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with CD20-positive B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma, and other blood cancers.

About the NP30179 study
The NP30179 study [NCT03075696] is a phase I/Ib, multicentre, open-label, dose-escalation study, evaluating the efficacy, safety, tolerability and pharmacokinetics of glofitamab. In this study, glofitamab is assessed as a single agent and in combination with Gazyva/Gazyvaro (obinutuzumab), following pre-treatment with a one-time, fixed dose of Gazyva/Gazyvaro, in people with relapsed or refractory B-cell non-Hodgkin lymphoma. Outcome measures include overall response rate, complete response rate per Lugano 2014 criteria, maximum tolerated dose, and tolerability.

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes idasanutlin, a small molecule which inhibits the interaction of MDM2 with p53; T-cell engaging bispecific antibodies, glofitamab and mosunetuzumab, targeting both CD20 and CD3, Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On June 12, 2020 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) ("Takeda") reported it will orally present the results of two studies at the 25th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, Takeda, JUN 12, 2020, View Source [SID1234561062]). Presentations are available online starting Friday, June 12, 2020, and include positive results from TOURMALINE-MM4, a Phase 3, randomized clinical trial evaluating the effect of single-agent oral NINLARO (ixazomib) as a first-line maintenance therapy in adult patients diagnosed with multiple myeloma who had not been treated with stem cell transplantation. Takeda is also presenting key insights from the US MM-6 trial, which investigates the effectiveness and safety of an in-class transition to oral NINLARO in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients who have previously received a parenteral bortezomib-based triplet induction therapy.

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"The positive data from the Phase 3 trial evaluating NINLARO as a maintenance therapy in patients not eligible for stem cell transplantation showed significant improvement in progression-free survival"

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The TOURMALINE-MM4 trial achieved its primary endpoint, with treatment with NINLARO resulting in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation (hazard ratio [HR] 0.659; CI: 95; p <0.001). This corresponds to a 34% reduction in risk of progression or death in patients treated with NINLARO. The safety profile of NINLARO was consistent with previously reported results of single-agent NINLARO use and there were no new safety signals identified.

"There is a strong need for additional maintenance treatments for multiple myeloma, where currently approved options are limited," said Meletios Dimopoulos, MD, University of Athens School of Medicine and principal investigator of the TOURMALINE-MM4 trial. "Data from this Phase 3 clinical trial reinforce the role of proteasome inhibition as a maintenance therapy and suggest that longer duration of therapy can improve a response, in addition to extending it. These data could be highly impactful for those who currently have limited options, which is often the case with patients not eligible for a stem cell transplant."

Key findings of the TOURMALINE-MM4 trial, to be presented by Dr. Dimopoulos include:

The trial achieved its primary endpoint, with treatment with NINLARO resulting in a statistically significant and clinically meaningful improvement in PFS in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation (hazard ratio [HR] 0.659; CI: 95; p <0.001). Median PFS for patients in the NINLARO arm was 17.4 months compared to 9.4 months in the placebo arm. This corresponds to a 34.1% reduction in risk of progression or death in patients treated with NINLARO.
The secondary endpoint of overall survival (OS) is not yet mature and follow-up is ongoing.
The benefits of NINLARO maintenance were realized in the context of a well-tolerated safety profile and no adverse impact on patients’ quality of life.
The safety profile of NINLARO is consistent with previously reported results of single-agent NINLARO use and there were no new safety signals identified.
The most common treatment emergent adverse events (TEAEs) (with incidence ≥5% higher with ixazomib) were nausea, vomiting, diarrhea, rash, peripheral neuropathy (PN) and pyrexia.
Grade ≥3 TEAEs were experienced by 36.6% of patients receiving NINLARO versus 23.2% receiving placebo.
The rate of new primary malignancies was 5.2% versus 6.2% in the placebo arm.
Discontinuation of treatment due to TEAEs was low, at 12.9% in the NINLARO arm and 8% in the placebo arm.
The rate of on-study deaths was 2.6% in the NINLARO arm compared to 2.2% in the placebo arm.
Updated data from US MM-6 will also be presented orally at EHA (Free EHA Whitepaper). The trial revealed the in-class transition from treatment with parenteral bortezomib to a NINLARO-based treatment, taken by patients at home, allowed for prolonged proteasome inhibitor administration and resulted in an increase in overall response rate from 62% to 70% and an increase in complete response from 4% to 26%. These data suggest promising efficacy without impacting patients’ quality of life. The safety profile of NINLARO treatment in this setting is favorable with no unexpected safety signals identified in US MM-6.

"The positive data from the Phase 3 trial evaluating NINLARO as a maintenance therapy in patients not eligible for stem cell transplantation showed significant improvement in progression-free survival," said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. "Coupled with the US MM-6 trial results of in-class transition from parenteral to oral proteasome inhibitor, these data add to the body of evidence supporting NINLARO could be an effective, tolerable and convenient medicine for patients with multiple myeloma that allows for an increased duration of treatment with proteasome inhibitors resulting in better outcomes."

NINLARO is currently approved in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed / refractory multiple myeloma in more than 65 countries.

About the TOURMALINE-MM4 Trial

TOURMALINE-MM4 is a randomized, placebo-controlled, double-blind Phase 3 study of 706 patients, designed to determine the effect of single-agent oral NINLARO (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in adult patients newly diagnosed with multiple myeloma not treated with stem cell transplant, who have completed 6-12 months of initial therapy and achieved a partial response or better. For additional information, please visit View Source

About the US MM-6 Trial

US MM-6 is an ongoing open-label, single-arm, multicenter study evaluating the effectiveness and safety of an in-class transition to NINLARO (ixazomib) in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who received bortezomib-based triplet induction. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include duration of therapy and duration of response. For additional information: View Source

About Multiple Myeloma

Multiple myeloma is a life-threatening rare blood cancer that arises from the plasma cells, a type of white blood cell that is made in the bone marrow. These plasma cells become abnormal, multiply and release a type of antibody known as a paraprotein, which causes symptoms of the disease, including bone pain, frequent or recurring infections and fatigue, a symptom of anemia. These malignant plasma cells have the potential to affect many bones in the body and can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count. The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission. Nearly 230,000 people around the world live with multiple myeloma, with approximately 114,000 new cases diagnosed globally each year.

About NINLARO (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is currently approved in more than 65 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

NINLARO (ixazomib): GLOBAL IMPORTANT SAFETY INFORMATION

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Thrombotic microangiopathy, sometimes fatal, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TPP/HUS and stop NINLARO if diagnosis is suspected. If the diagnosis of TPP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TPP/HUS is not known.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and female patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS

The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.

For European Union Summary of Product Characteristics: View Source
For US Prescribing Information: View Source
For Canada Product Monograph: View Source

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

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