December 2017 – Page 47 – 1stOncology™: Cancer Intelligence Service

New Data from Ivosidenib Phase 1 Dose-Escalation and Expansion Trial Demonstrate Durable Responses in Patients with IDH1m Relapsed or Refractory AML

On December 11, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported new efficacy and safety data from the ongoing Phase 1 dose-escalation and expansion study evaluating oral ivosidenib (AG-120) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, DEC 11, 2017, View Source [SID1234522571]). Ivosidenib is an investigational, first-in-class, oral, targeted inhibitor of the mutant IDH1 enzyme. Data in an oral session at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition demonstrated a complete response (CR) and CR with partial hematologic recovery (CRh) rate of 30.4% and an overall response rate (ORR) of 41.6% in the primary analysis set of 125 patients with R/R AML who received ivosidenib at 500 mg once daily and received their first dose at least 6 months prior to the May 12, 2017 analysis cutoff date. The CR+CRh rate is the primary endpoint of the study.

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"New ivosidenib data from the expansion phase of the Phase 1 study is compelling and demonstrates impressive single-agent efficacy with durable responses in these high-risk relapsed or refractory AML patients," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "Important measures of clinical benefit for patients treated with ivosidenib were also observed and include increases in transfusion independence and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients."

A total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated on the Phase 1 study, which included 78 patients in the dose-escalation portion and 180 patients from four dose-expansion Arms. Enrollment to the study is closed. This is the first presentation of data from the dose-expansion portion of the study. Safety data reported include all treated patients, and includes those who received ivosidenib at total daily doses ranging from 200 mg to 1200 mg in dose-escalation and 500 mg daily in dose expansion. A maximum tolerated dose was not reached in the dose-escalation portion of the trial. The primary analysis set is comprised of 125 R/R AML patients (92 patients from Arm 1 of the expansion and 33 patients from the dose-escalation who met the eligibility criteria for Arm 1 and received ivosidenib at 500 mg once daily) who were enrolled at least 6 months prior to the primary analysis cutoff date of May 12, 2017. The median age of these patients is 67 (ranging from 18-87), and the median number of prior regimens is two (ranging from one to six).

"These data form the core of the efficacy analysis for our ivosidenib NDA submission, which is on track for the end of the year," said Chris Bowden, M.D., chief medical officer of Agios. "We believe that these data validate the potential for ivosidenib to be a first-in-class therapy for patients with R/R AML and an IDH1 mutation."

Safety Data
A safety analysis conducted for all 258 treated patients as of the data cut-off showed that ivosidenib continues to demonstrate a favorable safety profile. The most common adverse events (AEs) regardless of causality were diarrhea (33.3%), leukocytosis (30.2%), nausea (29.5%), fatigue (28.7%) and febrile neutropenia (25.2%).

Among the 125 R/R AML patients from the primary analysis set, adverse events of interest were the following:

8% reported Grade ≥3 leukocytosis, which was managed with hydroxyurea. No cases were fatal.
8% reported Grade 3 QT prolongation. Ivosidenib was reduced in one patient and held in five patients (for any grade of QT prolongation), and no cases were Grade 4 or fatal.
9.6% reported IDH-differentiation syndrome (IDH-DS), which was managed with corticosteroids and diuretics. None were Grade 4 or fatal.
Efficacy Data
Data from 125 R/R AML patients from the primary analysis set demonstrated a combined CR+CRh rate of 30.4% [95% CI 22.5, 39.3], which is the primary endpoint of the study. The CR rate was 21.6% (27 of 125 patients) [95% CI 14.7, 29.8] and the CRh rate was 8.8% (11 of 125 patients). CRh (complete remission with partial hematological recovery) is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

Overall response rate (ORR) was 41.6% (52 of 125 patients).
Median duration of response was 9.3 months [95% CI 5.6, 18.3] for patients who achieved a CR, 8.2 months [95% CI 5.5, 12.0] for patients who achieved a CR/CRh and 6.5 months [95% CI 4.6, 9.3] for all patients who responded.
Median time to first response was 1.9 months (0.8-4.7) for all patients who responded, median time to CR was 2.8 months (0.9-8.3) for patients who achieved a CR, and median time to CR/CRh was 2.7 months (0.9-5.6) for patients who achieved a CR/CRh.
At the time of the data cut-off, median overall survival (OS) as observed in the study has not yet been reached for patients who achieved a CR/CRh. OS was 9.3 months [95% CI 3.7, 10.8] for non-CR/CRh responders, 3.9 months [95% CI 2.8, 5.8] for non-responders, and 8.8 months [95% CI 6.7, 10.2] overall.
Of the patients who were transfusion dependent at baseline and achieved a CR, 100% became independent of platelet transfusions and 84.6% became independent of red blood cell (RBC) transfusions during any 56-day post baseline period.
Of the patients who were transfusion dependent at baseline and achieved a CRh, 71.4% became independent of platelet transfusions and 75.0% became independent of RBC transfusions during any 56-day post baseline period. Transfusion independence was also seen among non-CR/CRh responders and non-responders. Non-CR/CRh responders include patients with CR with incomplete hematologic recovery (CRi), CR with incomplete platelet recovery (CRp) and morphologic leukemia-free state (MLFS) who are not CRh.
Response in Untreated AML and MDS
An efficacy analysis was also presented for 34 untreated AML patients not eligible for standard of care therapies in expansion Arm 2 and from dose escalation whose starting dose was 500 mg daily and 12 myelodysplastic syndrome (MDS) patients in expansion Arm 3 and from dose escalation whose starting dose was 500 mg daily.

Data from 34 untreated AML patients demonstrated a 55.9% ORR and a CR rate of 20.6%. The median duration of response was 9.2 months [95% CI 1.9, NE], and median duration of CR has not yet been reached.
Data from 12 MDS patients demonstrated a 91.7% ORR and a CR rate of 41.7%.
Clinical Development in AML
Ivosidenib continues to be studied in the following ongoing clinical trials in AML:

Phase 3 AGILE study evaluating the safety and efficacy of ivosidenib + azacitidine vs. placebo + azacitidine in adults with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy
Phase 1b study of either ivosidenib or enasidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML
Phase 1/2 study of either ivosidenib or enasidenib in combination with azacitidine in newly diagnosed AML
Agios is on track to file a New Drug Application (NDA) for ivosidenib with the U.S. Food and Drug Administration by the end of 2017.

About the Phase 1 Trial for Ivosidenib in Advanced Hematologic Malignancies
Ivosidenib (AG-120) is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:

Arm 1: IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
Arm 2: untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

Investor Event and Webcast Information
Agios will host an investor event on Monday, December 11, 2017 beginning at 8:00 p.m. ET in Atlanta to review data presented at ASH (Free ASH Whitepaper). The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com.

Data from Phase 1 Studies of Ivosidenib or Enasidenib in Combination with Full Doses of Standard of Care Chemotherapy Demonstrate Tolerability and Preliminary Clinical Activity in Newly Diagnosed AML Patients With an IDH Mutation

On December 11, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported data from two studies evaluating ivosidenib (AG-120) and an investigational use of IDHIFA (enasidenib) in patients with newly diagnosed acute myeloid leukemia (AML) and an isocitrate dehydrogenase (IDH)1 or IDH2 mutation (Press release, Agios Pharmaceuticals, DEC 11, 2017, View Source [SID1234522573]). The data were presented as part of the scientific program at the 59thAmerican Society of Hematology Annual Meeting in Atlanta.

"The totality of the data presented at ASH (Free ASH Whitepaper) demonstrate the potential benefit of IDHm inhibitors in the frontline setting for patients with AML," said Eytan Stein, M.D., study investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "The Phase 1 frontline combination trials showed that ivosidenib and enasidenib are well tolerated when combined with standard induction chemotherapy or azacitadine and both trials demonstrated early encouraging signs of efficacy. I look forward to evaluating both ivosidenib and enasidenib in late-stage, placebo-controlled clinical trials to understand the full impact of these medicines on newly diagnosed AML patients."

Combination with Standard Induction Chemotherapy
The first presentation, given by Dr. Stein, evaluated ivosidenib or enasidenib in combination with standard induction chemotherapy in patients with newly diagnosed AML and an IDH1 or IDH2 mutation. During induction, patients received either 500 mg of ivosidenib and 7 + 3 standard chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) (n=32) or 100 mg of enasidenib and 7 + 3 standard chemotherapy (n=56). Of these patients, 69% in the ivosidenib arm and 57% in the enasidenib arm had de novo AML, while the remaining patients had secondary AML (sAML). For patients with sAML, 40% in the ivosidenib arm and 63% in the enasidenib arm had received prior hypomethylating agent therapy. After induction, patients could receive up to four cycles of consolidation chemotherapy while continuing ivosidenib or enasidenib. Patients who achieved a complete response (CR) or a complete response with incomplete neutrophil or platelet recovery (CRi/CRp) after consolidation could continue to take single agent ivosidenib or enasidenib daily for up to two years from day one of induction.

Ivosidenib Results
In the ivosidenib arm, the most common Grade 3 or higher non-hematologic adverse events during the induction period were febrile neutropenia (60%), blood bilirubin increased (9%), hypertension (9%), colitis (9%), increased alanine aminotransferase (9%) and increased aspartate aminotransferase (9%). The 30 and 60-day mortality rates were both 6%, and there were no dose-limiting toxicities. The median time to absolute neutrophil count (ANC) recovery (>500/µL) was 28.5 days (95% CI 27,34). Median time to platelet recovery (>50,000/µL) was 28 days (95% CI 26,34).

The CR+CRi/CRp rate for de novo patients was 91% (19/21) and 44% (4/9) for sAML patients. The overall best response of CR+ CRi/CRp rate for all patients was 77% (23/30).

Enasidenib Results
In the enasidenib arm, the most common Grade 3 or higher non-hematologic adverse events during the induction period were febrile neutropenia (63%), blood bilirubin increased (9%), hypertension (9%) and bacteremia (9%). The 30 and 60-day mortality rates were 5% and 7%, respectively. There was one dose-limiting toxicity in the enasidenib combination arm consisting of persistent Grade 4 thrombocytopenia lasting beyond 42 days from the start of induction. The median time to ANC recovery (>500/µL) was 34 days (95% CI 29,35). Median time to platelet recovery (>50,000/µL) was 33 days (95% CI 29,50).

The CR+CRi/CRp rate for de novo patients was 67% (18/27) and 57% (13/23) for sAML patients. The overall best response of CR+CRi/CRp rate for all patients was 62% (31/50).

"The early results from these studies of ivosidenib and enasidenib in combination with traditional frontline AML treatment are highly encouraging and support the strategy to advance IDHm inhibitors into the newly diagnosed setting," said Chris Bowden, M.D., chief medical officer of Agios. "We are focused on evaluating the IDHm inhibitors in late-stage studies that span the entire frontline setting with our ongoing Phase 3 AGILE study of ivosidenib in combination with azacitidine versus azacitidine and a planned Phase 3 study of ivosidenib and enasidenib in combination with 7+3 intensive chemotherapy."

Combination with Azacitidine
The second presentation, given by Courtney DiNardo, M.D., evaluated an investigational use of enasidenib or ivosidenib in combination with azacitidine in patients with newly diagnosed AML unable to receive intensive chemotherapy. In the study, patients received 100mg (n=3) or 200mg (n=3) of enasidenib daily plus azacitidine or 500 mg of ivosidenib (n=11) plus azacitidine. At the data cutoff, 11 patients remained on the study (3 enasidenib, 8 ivosidenib).

Enasidenib Results

For patients receiving the enasidenib combination, the most common Grade 3-4 hematologic adverse event was neutropenia (33%, 2/6). The most common Grade 3-4 non-hematologic adverse events were pneumonia (33%, 2/6) and hyperbilirubinemia (33%, 2/6). IDH differentiation syndrome was reported in one patient.

Four of six patients had a response, including two CRs, one partial response (PR) and one morphologic leukemia-free state (MLFS).

Ivosidenib Results
For patients receiving the ivosidenib combination, the most common Grade 3-4 hematologic adverse events were anemia (18%, 2/11) and febrile neutropenia (18%, 2/11) with neutropenia and thrombocytopenia each with one event (9% each). The most common Grade 3-4 non-hematologic adverse event was pneumonia (18%, 2/11). IDH differentiation syndrome was reported in one patient.

Eight of 11 patients had a response, including four CRs, one CRi, one PR and two MLFS.

Neither IDHIFA nor ivosidenib are approved for the treatment of patients with newly diagnosed AML or approved in combination with azacitidine.

About IDHIFA

IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.

Important Safety Information

WARNING: DIFFERENTIATION SYNDROME
Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure
LACTATION
Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

Annual Report 2017 (The facing page A3size)

On December 11, 2017 Nippon Kayaku presented Annual Report 2017 (Presentation, Nippon Kayaku, DEC 11, 2017, View Source;sid=43565&code=4272 [SID1234522559]).

TG Therapeutics, Inc. Announces Preclinical & Clinical Data Presentations at the 59h American Society of Hematology Annual Meeting

On December 11, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation of six posters highlighting preclinical and clinical data sets for TGR-1202 (umbralisib), the Company’s once-daily PI3K delta inhibitor, and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, currently being held at the Georgia World Congress Center in Atlanta, Georgia (Press release, TG Therapeutics, DEC 11, 2017, View Source [SID1234522557]).

Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are very pleased by the data presented yesterday and today during the ASH (Free ASH Whitepaper) annual meeting. The preclinical data help us to better understand the difference between TGR-1202 and other agents in the class and offers a more complete rationale for the differentiated safety profile seen in the clinic. With the updated and expanded integrated safety analysis of TGR-1202 alone and in combination with other agents, we believe we have provided the long-term follow-up sufficient to allay any lingering safety concerns related to TGR-1202 caused by the toxicity profile of first generation PI3K delta inhibitors." Mr. Weiss continued, "In 2018, with registration-directed data expected in CLL and NHL, our focus will turn to showcasing the efficacy of TGR-1202 and our proprietary combination of TG-1101 plus TGR-1202, our U2 combination, ideally leading to NDA/BLA filings in CLL and NHL."

The following summarizes the highlights from each poster presented at the ASH (Free ASH Whitepaper) 2017 meeting.

Clinical Data Presentations:

An Integrated Safety Analysis of the Next Generation PI3K Delta Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

This presentation includes data that were pooled from 5 completed or ongoing Phase 1 or 2 studies containing TGR-1202, including a total of 347 patients with relapsed or refractory hematologic malignancies. Patients were heavily pretreated, with 50% of patients having seen 3 or more prior lines of therapy.