The FDA has granted permission for enrollment to resume in the monotherapy phase 1a portion of the phase 1/2 TakeAim Leukemia trial (NCT04278768) evaluating the safety and efficacy of emavusertib (previously CA-4948) in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS).

the partial clinical hold the FDA placed on the trial

 in April 2022 is still in effect for the phase 1b portion of the trial investigating emavusertib in combination with azacitidine (Vidaza) or venetoclax (Venclexta).

 The phase 2a dose-expansion portion of the trial also remains under partial hold until phase 1a is complete and the FDA grants approval to proceed to the next phase.

The FDA reviewed additional data provided by the Curis, Inc., related to the risk of rhabdomyolysis associated with emavusertib. The agency also examined Curis’ strategy for utilizing objective laboratory measurements to identify and manage rhabdomyolysis, if detected.

As part of the agreement between the FDA and Curis, the monotherapy portion of the trial will enroll at least 9 additional patients at 200 mg of emavusertib.

“We are pleased to announce the results of the FDA's review and to have addressed potential concerns about the identification and management of rhabdomyolysis,” James Dentzer, president and chief executive officer of Curis, stated in a press release. “We are working with our clinical sites to quickly resume enrollment of additional patients.”

When the FDA placed the partial clinical hold on the TakeAim Leukemia trial, the agency requested additional information from the study, including findings associated with the death of a patient with relapsed/refractory AML who experienced rhabdomyolysis, among other conditions. Previous results identified rhabdomyolysis as a dose-limiting toxicity associated with emavusertib.

the FDA also placed a partial clinical hold on the phase 1/2 TakeAim Lymphoma trial (NCT03328078)

 assessing emavusertib in patients with relapsed or refractory B-cell malignancies.

the FDA lifted the partial clinical hold on TakeAim Lymphoma

 after Curis and the FDA agreed on a strategy for rhabdomyolysis identification and management, along with an understanding that the company will enroll at least 9 additional patients at the 200 mg dose level of emavusertib in combination with ibrutinib (Imbruvica).

The open-label, dose-escalation, dose-expansion TakeAim Leukemia trial assigned patients with relapsed/refractory AML or MDS to receive emavusertib alone or in combination with azacitidine or venetoclax. If the partial clinical hold is lifted on the combination portion of the trial, investigators plan to expand to 5 cohorts: emavusertib monotherapy in patients with AML patients with spliceosome and 

 mutations; emavusertib monotherapy in patients with MDS and spliceosome mutations; and emavusertib combination therapy with azacitidine or venetoclax in patients without spliceosome or 

The primary objectives of the study include the safety, maximum tolerated dose, recommended phase 2 dose, and signals of activity for emavusertib.

After the partial clinical hold was lifted on the monotherapy portion of the TakeAim Leukemia study, Curis revised its timeline for the release of updated preliminary clinical data to 2023.

FDA Allows Patient Enrollment to Resume in Monotherapy Dose Escalation of Emavusertib in TakeAim Leukemia Study. News release. Curis. August 30, 2022. Accessed August 30, 2022. 

Curis announces FDA partial clinical hold for TakeAim Leukemia study of emavusertib (CA-4948). News release. Curis, Inc.; April 4, 2022. Accessed August 30, 2022. 

Curis announces FDA partial clinical hold for TakeAim Lymphoma study of emavusertib (CA-4948). News release. Curis, Inc.; April 11, 2022. Accessed August 30 2022. 

FDA Lifts Partial Clinical Hold on the TakeAim Lymphoma Study of Emavusertib. News release. Curis, Inc. August 18, 2022. Accessed August 30, 2022. 

Articles

The FDA has granted permission for enrollment to resume in the monotherapy phase 1a portion of the phase 1/2 TakeAim Leukemia trial evaluating emavusertib in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.

FDA Allows Trial Enrollment to Resume for Single-Agent Emavusertib in AML/MDS

The combination of sotorasib (Lumakras) and the small molecule SHP2 inhibitor RMC-4630 led to an investigator-assessed objective response rate (ORR) of 27% (95% CI, 6%-61%) and 50% (95% CI, 12%-88%) in pretreated and KRAS G12C inhibitor–naïve patients with non–small cell lung cancer (NSCLC), respectively, according to findings from a phase 1b trial (NCT04185883).

The data, which were presented at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer, showed that among all enrolled patients with NSCLC (n = 11) who received the regimen, 3 experienced partial responses (PRs; 27%), 4 had stable disease (SD; 36%), and 4 experienced progressive disease (PD; 36%); this translated to a disease control rate (DCR) of 64% (n = 7). Within the KRAS G12C inhibitor–naïve population (n = 6), 3 PRs (50%) and 3 cases of SD (50%) were reported, translating to a DCR of 100%.

“Preclinical rationale and putative mechanisms of resistance support the combination of sotorasib with a SHP2 inhibitor,” Gerald S. Falchook, MD, director of the Sarah Cannon Research Institute at HealthONE, and coauthors, stated in the presentation. “The combination of sotorasib with a SHP2 inhibitor, RMC-4630, based on early data, appears safe and well tolerated in 

 p.G12C–mutated solid tumors. Additionally, promising and durable clinical activity was observed in patients with NSCLC, most notably in those who were KRAS G12C inhibitor naïve.”

Sotorasib is a specific and irreversible KRAS G12C inhibitor 

approved for the treatment of patients with previously treated 

. However, genomic alterations in the RTK pathway have been linked to acquired resistance mechanisms to the agent.

In mouse xenograft models, the addition of sotorasib to a SHP2 inhibitor reduced RTK signaling to RAS and enhanced antitumor activity.

The multicenter, open-label study enrolled patients with locally advanced or metastatic 

G12C–mutated solid tumors. Within the NSCLC cohort, patients must have received prior therapy with PD-1/PD-L1 inhibitors and/or platinum-based chemotherapy and targeted therapy. Treatment with a prior KRAS G12C inhibitor was allowed across all cohorts.

Part 1 consisted of the dose-exploration phase in which 27 patients received 960 mg of sotorasib once daily plus RMC-4630 in escalating weekly doses starting at 100 mg on days 1 and 2 or days 1 and 4 (n = 6), then 140 mg on days 1 and 2 (n = 10), and 200 mg on days 1 and 2 (n = 11).

The primary end points comprising safety included the identification of dose-limiting toxicities (DLTs), treatment-related adverse effects (TRAEs) and treatment-emergent AEs, as well as changes in vital signs, ECGs, and clinical laboratory tests. Secondary efficacy end points included the evaluation of pharmacokinetics, ORR, duration of response (DOR), time to response, DCR, duration of SD per RECIST v1.1 criteria, and overall survival.

The data cutoff was April 11, 2022, allowing for a median follow-up of 5.8 months.

Within the NSCLC cohort, the median age was 64 years (range, 51-78), 36% of patients (n = 4) were male, and all were prior smokers. Most patients had an ECOG performance status of 0 (n = 10; 90%). The most common site of metastasis was the brain (n = 7; 64%) followed by the liver (n = 3; 27%).

The median number of prior lines of therapy received was 3 (range, 1-6). Almost all patients had received a prior PD-1/PD-L1 inhibitor (n = 10; 91%), and approximately half (n = 5; 45%) had received a prior KRAS G12C inhibitor.

The median duration of treatment on the combination was 3.1 months (standard deviation, 2.7). At the time of data cutoff, 2 of 3 patients in PR had an ongoing response, with a DOR of more than 9.8 months and 6.9 months, respectively.

Additionally, 1 patient whose disease progressed on prior sotorasib experienced more than 30% tumor shrinkage at 5.5 months, with PD at 6.9 months.

“There were no clinically meaningful drug-drug interactions between sotorasib and RMC-4630, and the average sotorasib and RMC-4630 exposures were consistent with distributions observed in monotherapy studies,” the authors wrote.

Notably, at the two highest doses of RMC-4630, responders included 3 of 4 patients who were KRAS G12C inhibitor naïve.

Regarding safety, the most common TRAEs with the combination across the entire study population were edema (all grade, 30%), diarrhea (all grade, 26%; grade 3, 7%), dry mouth (all grade, 11%), fatigue (all grade, 11%), aspartate aminotransferase increase (all grade, 7%; grade 3, 4%), ascites (all grade, 4%; grade 3, 4%), colitis (all grade, 4%; grade 3, 4%), dyspnea (all grade, 4%; grade 3, 4%), hypertension (all grade, 4%; grade 3, 4%), and pleural effusion (all grade, 4%; grade 3, 4%).

“Sotorasib combined with RMC-4630 was safe and tolerable, with no grade 4 or fatal TRAEs and few TRAE-related discontinuations,” the authors wrote. “TRAEs were consistent with the known safety profile of sotorasib and RMC-4630. Edemas (peripheral and facial) were the most common TRAE; all were grade 1 or 2, and none led to discontinuation.

Across the 100-mg, 140-mg, and 200-mg dosing cohorts, TRAEs leading to sotorasib dose modification occurred in 17% (n = 1), 10% (n = 1), and 27% (n = 3) of patients, respectively; dose modifications with RMC-4630 occurred in 33% (n = 2), 10% (n = 1), and 36% (n = 4) of patients, respectively.

One patient each in the 100-mg and 140-mg cohorts experienced a DLT.

The combination is under further study in a phase 2 trial (NCT05054725) in patients with metastatic NSCLC who are KRAS G12C inhibitor naïve.

Falchook GS, Li BT, Marrone KR, et al. Sotorasib in combination with RMC-4630, a SHP2 inhibitor, in 

 p.G12C-mutated NSCLC and other solid tumors. Presented at: IASLC 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA03.03

The combination of sotorasib and the small molecule SHP2 inhibitor RMC-4630 led to an investigator-assessed objective response rate of 27% and 50% in pretreated and KRAS G12C inhibitor–naïve patients with non–small cell lung cancer, respectively.

Sotorasib Plus SHP2 Inhibition Elicits Promising Preliminary Activity in KRAS G12C–Mutated NSCLC

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasms (MPN) whose tumors harbored 

 mutations, according to data from a phase 1/2 trial (NCT04493138).

At a median follow-up of 13.2 months (95% CI, 4.6-21.7), the combination elicited a 90% overall response rate (ORR; n = 9/10). Among the 10 patients, 60% had a complete response in the marrow (mCR). Additionally, a complete response, a mCR with hematologic improvement (HI), and a HI were observed in 1 patient each. The median number of cycles to best response was 1 (range, 1-6) and the median duration of response (DOR) was 6.3 months (range, 1.6-14.3).

“[The] combination of quizartinib and azacitidine [is] active in MDS and MDS/MPN, [and] no dose-limiting toxicities [DLTs] were [observed] in [the] phase 1 dose-escalation portion [of the trial] up to doses of 60 mg daily [on] days 1 to 28,” study authors from The University of Texas MD Anderson Cancer Center wrote in a poster shared during the 2022 EHA Congress. “[The regimen had an] acceptable toxicity profile.”

Approximately 1% of patients with newly diagnosed MDS harbor 

 mutations, although the mutations occur in up to 19% of patients at the time of failure of a hypomethylating agent (HMA). Additionally, approximately 10% of patients with MDS/MPN harbor 

mutations; these mutations occur in 13% to 15% of those with chronic myelomonocytic leukemia (CMML).

The phase 1/2 trial evaluated the doublet in adult patients aged 18 years of age or older with HMA-naïve MDS or MDS/MPN with intermediate-2/high-risk disease per International Prognostic Scoring System (IPSS) or higher than 5% blasts; or any MDS or MDS/MPN following failure on HMA treatment. All patients were required to have a 

-ITD/D835 mutation; they also needed to have an ECOG performance status of 0 to 2.

Patients were excluded from the study if they had a QTcF of more than 450 msec; a history of clinically significant ventricular fibrillation, torsades de pointes, sustained ventricular tachycardia, or long QT syndrome; a known history of second- or third-degree heart block; a complete left bundle branch or bifascicular block; or atrial fibrillation documented within 2 weeks of study entry.

Patients enrolled to the dose-escalation portion of the trial received either 30 mg (n = 3), 40 mg (n = 3), or 60 mg (n = 4) of oral quizartinib per day on days 1 through 28, in combination with 75 mg/m

 of azacitidine daily on days 1 through 5 of each 28-day cycle.

The primary end points of the dose-escalation portion of the trial were to evaluate safety and tolerability, and determine the maximum tolerated dose (MTD) of quizartinib. Secondary end points included ORR per International Working Group 2006 criteria, overall survival (OS), DOR, relapse-free survival, and leukemia-free survival.

At data cutoff, total of 10 patients were enrolled to the trial,; 9 patients were included in the dose-escalation portion of the research and 1 was included in dose-expansion portion. Half of all patients had intermediate-2 risk disease, and the other half had intermediate-1 risk disease per IPSS.

Seven patients presented with CMML, 2 had MDS, and 1 had atypical chronic myeloid leukemia. Six patients harbored 

 mutations. Eight patients had normal cytogenetics at baseline, 1 had complex cytogenetics, and 1 had monosomy 7 cytogenetics. The median absolute neutrophil count (ANC) was 10.68 x 10

 (range, 0.33-113.8), the median platelet count was 110 x 10

 (range, 34-536), the median hemoglobin level was 9.6 g/dL (range, 7-10.3), and the median bone marrow blasts was 8% (range, 2%-15%).

Additional data showed that the combination resulted in a median OS of 17.35 months (95% CI, 6.8-28.3). Platelet recovery to more than 50 x 10

/L by day 28 of therapy occurred in 67% and 56% of patients, respectively. Furthermore, ANC recovered to 1 x 10

At the time of data cutoff, 1 patient remained on study treatment. Reasons for discontinuation included moving to allogeneic stem cell transplant (n = 4), disease relapse (n = 1), disease progression (n = 2), and patient/physician preference (n = 2). Patients received a median of 6 (range, 1-11) cycles of treatment.

No DLTs were reported in the dose-escalation phase of the research. However, 2 patients required dose reductions of quizartinib during cycle 3 or later because of cytopenias. Additionally, 3 patients needed dose reductions of azacitidine due to cytopenias. No early mortality was reported at weeks 4 and 8.

The most frequent grade 1/2 adverse effects reported with the doublet included constipation (n = 6), oral mucositis (n = 3), diarrhea (n = 2), fatigue (n = 2), nausea (n = 2), arthralgia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), injection site reaction (n = 1), and skin infection (n = 1). The most common grade 3 AEs were thrombocytopenia (n = 3), anemia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), chest pain (n = 1), and febrile neutropenia (n = 1).

The dose-escalation phase of the research is ongoing to further evaluate the safety and efficacy of the combination, according to study authors. Additional research on lower dose levels of 40 mg of quizartinib per day are warranted.

Abuasab T, Jabbour E, Short N, et al. Initial results of phase I/II study of azacitidine in combination with quizartinib for patients with myelodysplastic syndrome and myelodysplastic/myeloproliferative neoplasm with 

 mutation. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P754.

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome and myelodysplastic syndrome/myeloproliferative neoplasms whose tumors harbored FLT3 or CBL mutations, according to data from a phase 1/2 trial (NCT04493138).

Pipeline Report: August 2022

Articles

FDA Allows Trial Enrollment to Resume for Single-Agent Emavusertib in AML/MDS

Sotorasib Plus SHP2 Inhibition Elicits Promising Preliminary Activity in KRAS G12C–Mutated NSCLC