Rhenium-186 nanoliposome (186RNL) administered at doses exceeding 100 Gy demonstrated promising safety and efficacy results in patients with recurrent glioma, according to phase 1 findings from the ReSPECT-GBM trial (NCT01906385).

Lead author Andrew J. Brenner, MD, PhD, a neuro-oncologist with Mays Cancer Center at UT Health San Antonio, presented findings at the ESMO Congress 2022 showing that 186RNL extended overall survival (OS) when patients receive at least 100 Gy radiation. The median OS was 22.9 months (95% CI, 8.8-42.3) for those who received at least 100 Gy of 186RNL compared with just 5.6 months (95% CI, 1.6-9.4) for those who received a smaller dose. Median OS for the entire cohort (N = 23) was 9.4 months (95% CI, 5.8-13.2). Three patients in the 100 Gy or higher group remain alive compared with no patients in the lower group.

“Those patients who live longest were the ones who had the highest amount of [tumor] coverage and the highest absorbed doses [of radiation],” Brenner said. “We saw a statistically significant loss of benefit in [those who received the] therapeutic dose vs subtherapeutic [dose]. In cohorts 5 to 7, the therapy dose was achieved in 80% of patients and increasing drug volume and radiation correlated with improved OS.”

186RNL comprises radioactive rhenium-186 placed inside of a nanoliposome and administered by convection-enhanced delivery. The nanoliposomes help carry radiation to tumor cells where the radioisotope then releases radiation to attack those cells directly and sparing normal cells.

Investigators recruited 23 total patients, 65% of whom were male. Patients received an average of 1.6 prior treatments (range, 1-3). Patients were stratified into 8 dose levels ranging from 1.0 mCi to 22.3 mCi. Treatment volume increased from 0.6 mL to 8.8 mL. Mean tumor volume was 8.3 mL and the maximum average absorbed radiation dose to the tumor was 584 Gy.

Five (23%) patients received prior bevacizumab (Avastin). However, bevacizumab exposure was an excluding factor in the final 3 cohorts because investigators noted poor delivery of radiation in the first 5 patients.

Brenner noted that the population had “less than ideal prognostic factors.” Thirteen (57%) had unmethylated MGMT status vs 17% methylated and 26% undeclared. Twenty-one (91%) patients had grade IV disease; 2 (9%) had grade III.

 and 2 were negative. The average tumor volume was 8.1 cm

All patients received computerized treatment planning and placement of up to 4 intracranial catheters. Each patient received a single administration of 186RNL by convection enhanced delivery. Investigators assessed dosimetry and radiation distribution following treatment on days 1 to 8 using whole body planar and SPECT/CT imaging. Patients were followed for safety, sufficiency of radiation delivery, and OS.

Brenner noted that tumor coverage correlated with response. In 1 patient, tumor volume was 6.5 mL and coverage was greater than 90%.

“We saw a little bit of increase in the [tumor] size…through the first 3 months with possible pseudoprogression,” he said. “But by day 362, this had significantly decreased in size and the patient had survival beyond 950 days.”

Investigators observed no dose limiting toxicities and most adverse events (AEs) were grade 1/2. For grade 3 AEs, investigators observed 1 incident of osteonecrosis in the left shoulder, 2 seizures, 2 vasogenic cerebral edemas, and 1 pneumonia.

In his concluding remarks, Brenner noted that no dosing failures were reported and that single-administration with 186RNL resulted in approximately 20 times more absorbtion vs extended beam radiation therapy at 740 Gy vs 35 Gy. A phase 2 trial is anticipated which will evaluate 22.3 mCi in 8.8 mL for patients with recurrent glioma less than 20 mL in total volume.

Giuseppe Minniti, MD, PhD, a clinical associate professor and neuro-oncology consultant with the Department of Neurosciences, Neurosurgery at the University La Sapienza in Rome, Italy, offered perspective on the results. He said many questions remain to be answered including the optimal number of catheters and whether tumor geometry characteristics could affect dose distribution. Nonetheless, he called the findings “very promising.”

“We don’t see often [this] long survival in the [recurrent] setting,” he said. “But it’s quite interesting that there is a significant difference between the survival according to the radiation dose.”

Brenner AJ, Phillips WT, Bao A, et al. The ReSPECT-GBM™ phase I/IIa trial of rhenium-186 nanoliposome (186RNL) in recurrent glioma via convection enhanced delivery (CED) and planned phase IIb trial. Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract 2770.

Articles

Rhenium-186 nanoliposome administered at doses exceeding 100 Gy demonstrated promising safety and efficacy results in patients with recurrent glioma.

Higher-Dose Rhenium-186 Nanoliposome Demonstrates OS Advantage in Recurrent Glioma

Azacitidine (Onureg) plus venetoclax (Venclexta) showed encouraging activity in patients with high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CML), according to findings from a phase 1/2 trial (NCT04160052) published in 

Patients (N = 23) received intravenous or subcutaneous 75 mg/m

 azacitidine for 5 days and oral 100 mg to 400 mg venetoclax for 7 to 14 days. In phase 1 results at a median follow-up of 13.2 months (interquartile range, 6.8-18.3), the overall response rate (ORR) was 87% (95% CI 66%–97%).

The maximum tolerated dose (MTD) was not reached. Investigators established the recommended phase 2 dose (RP2D) as 75 mg/m

 azacitidine for 5 days plus 400 mg venetoclax for 14 days.

Venetoclax is a first-in-class agent that selectively binds to and inhibits the BCL2 protein, which prevents some hematologic cancers from undergoing apoptosis. The agent is approved as a monotherapy for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma and in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older or with comorbidities that preclude use of intensive induction chemotherapy.

Investigators at the University of Texas MD Anderson Cancer Center enrolled adult patients with treatment-naive or relapsed/refractory high-risk MDS or CML and bone marrow blasts of more than 5% from November 2019 to December 2019. Seventeen patients (74%) were naïve to hypomethylating agents, and 6 patients (26%) had failed on a hypomethylating agent. Eighteen patients (78%) were male, 21 patients (91%) were White, and 2 patients (9%) were Asian.

The primary outcome was safety and tolerability. Investigators also sought to determine the MTD and RP2D of the azacytidine/venetoclax combination using a 3 + 3 study design.

The most common grade 3/4 treatment-emergent adverse effects were neutropenia (39%), thrombocytopenia (39%), lung infection (30%), and febrile neutropenia (17%). Investigators reported 3 deaths due to sepsis during the study, none of which were related to the treatment.

the FDA granted breakthrough therapy designation (BTD) to azacytidine/venetoclax combination or the treatment of adult patients with previously untreated intermediate-, high- and very high-risk MDS

 per the revised International Prognostic Scoring System (IPSS-R).

Results from the phase 1b M15-531 study (NCT02942290) supported the BTD. M15-531 is an ongoing study investigating the safety and pharmacokinetics of venetoclax plus azacitidine in approximately 137 patients with treatment-naïve, higher-risk MDS. The study was initiated to address the short median overall survival (OS) of the population, which is about 18 months.

The co-primary end points include area under the curve for both agents, maximum plasma concentration, time of maximum plasma concentration, half-life for azacitidine, clearance for azacitidine, and the RP2D.

Treatment with venetoclax plus azacitidine induced an ORR of 77%, which included complete responses (CR) in 42% and marrow CRs in 35%. Of the patients who achieved a CR, 40% had CR with hematological improvement. Responses lasted for a median duration of 14.8 months (95% CI, 12.9–not estimable [NE]). The median OS was not reached (95% CI, 16.2-NE). The median progression-free survival was 17.5 months (95% CI, 14.5-NE).

The analysis included 57 patients followed for a median of 13.0 months (95% CI, 11.3-15.6). The population was largely male (75%) and had a median age of 71 years (range, 26-85 years). Additionally, 89% of patients had an ECOG performance status of 0 or 1.

the FDA removed a partial clinical hold on the phase 3 ENHANCE trial (NCT04313881)

 evaluating magrolimab plus azacitidine vs azacitidine plus placebo in untreated patients with MDS and AML.

 The agency paused the study in January 2022 because of an apparent imbalance in investigator-reported, suspected unexpected serious adverse reactions. Although no clear trend in toxicities or new safety signals had been observed by the company at the time, the hold was placed on all ongoing studies that were evaluating the combination on a global scale.

Bazinet A, Darbaniyan F, Jabbour E, et al. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. 

. 2022:S2352-3026(22)00216-2. doi:10.1016/S2352-3026(22)00216-2

FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. July 21, 2021. Accessed September 7, 2022. 

Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. 

. 2020;136(suppl 1):55–57. doi:10.1182/blood-2020-139492

FDA lifts partial clinical hold on MDS and AML magrolimab studies. News release. Gilead Sciences, Inc. April 11, 2022. Accessed September 7, 2022. 

Azacitidine plus venetoclax showed encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia.

Azacitidine/Venetoclax Combo Delivers Promising Early Results in High-Risk CML, MDS

The FDA has granted an orphan drug designation to AVA6000, a modified form of doxorubicin, for the treatment of patients with soft tissue sarcoma, according to a press release issued by Avacta Group plc.

AVA6000 is a therapeutic product based on proprietary pre|CISION technology that contains a substrate that is sensitive to cleavage by fibroblast activation protein α (FAP).

 Specifically, the agent is comprised of a doxorubicin molecule that is covalently bonded to a dipeptide, which is designed to be susceptible to hydrolysis by FAP but is resistant to hydrolysis by closely related and wider mammalian peptidases.

The agent can directly deliver doxorubicin to the tumor microenvironment, while exposing the patient to fewer associated adverse effects. The primary mechanism of action of doxorubicin is thought to encompass stabilization of a topoisomerase-II-DNA cleavable complex through non-specific DNA-intercalation.

“We are delighted to receive orphan drug designation from the FDA for AVA6000, which is a reflection of the high quality of the preclinical data and the potential benefit the pre|CISION platform can bring to cancer patients,” Dr Alastair Smith, chief executive officer of Avacta Group, stated in a press release.

 “This designation provides tax credits and other incentives for drug developers addressing rare diseases. Most notably, the orphan drug designation will give Avacta, if AVA600 is approved for treatment of soft tissue sarcoma, 7 years of market exclusivity in the United States, which is a significant commercial advantage.”

In human tumor cell lines, in vitro cytotoxicity assessments revealed that AVA6000 was between 80-fold and 4000-fold less cytotoxic than doxorubicin.

 Many in vivo studies done in tumors with high FAP levels have demonstrated that AVA6000 resulted in a significant reduction in tumor volume and increase in survival in a dose-dependent manner.

Specifically, in a PDX model of osteosarcoma, the agent was found to decrease tumor volume; no significant effect was observed with doxorubicin.

In an open-label, first-in-human, phase 1 study (NCT04969835), investigators will examine the safety, tolerability, pharmacokinetics, and early efficacy of AVA6000 in patients with metastatic solid tumors.

The trial enrolled patients who were at least 18 years of age and who had histological or cytologic confirmation of locally advanced and/or metastatic pancreatic cancer, colorectal cancer, non–small cell lung cancer, squamous cell carcinoma of head and neck, ovarian cancer, breast cancer, soft tissue sarcoma, and bladder cancer who have relapsed or progressed on standard-of-care treatment or who are intolerant or not amenable to such treatment.

Patients needed to have a life expectancy of longer than 12 weeks, an ECOG performance status of 0 or 1, and acceptable hematologic, liver, and renal function.

If patients received trastuzumab (Herceptin) within 7 months of the planned day 1 of cycle 1 of infusion with AVA6000, had clinically significant or untreated central nervous system metastases in need of treatment, leptomeningeal disease, a history of an active other malignancy, or uncontrolled hypertension, they were excluded.

In the phase 1a portion of the research, participants will be administered escalating doses of AVA6000 in accordance with a 3+3 design, with a starting dose of 80 mg/m

 once every 3 weeks beginning on day 1 of cycle 1. Treatment was given until progressive disease, intolerable toxicities, withdrawal from treatment for other reason, maximum lifetime cumulative exposure to doxorubicin, or death.

For phase 1b, participants will be given the recommended phase 2 dose (RP2D) of the investigative agent once every 3 weeks beginning on day 1 of cycle 1. One of 3 tumor types will be selected based on the evaluation of the phase 1a findings.

The primary outcome measures of the study include the number of patients with dose-limiting toxicities (DLTs), percentage of those with DLTs of AVA6000 during the DLT period, identification of the maximum tolerated dose or the RP2D, and the percentage of patients with adverse effects at the RP2D of the agent in tumor-specific expansion arms.

Secondary outcome measures include maximum drug concentration of AVA6000 and doxorubicin, area under the concentration vs time curve of the 2 agents, elimination half-life of the agents, renal clearance of the agents, objective response rate, duration of response, progression-free survival, and overall survival.

In August 2021, the company announced that the first patient had received their first dose of AVA6000 at The Royal Marsden NHS Foundation Trust.

 In June 2022, it was announced that the phase 1 trial would advance to the third dose cohort.

This decision followed a review done by a Safety Data Monitoring Committee (SDMC) comprised of clinicians recruiting patients who examined safety data from the second cohort of the trial who received AVA6000 at 120 mg/m

. The committee recommended that the trial continue as planned and escalate to the next dose of 160 mg/m

“The recommendation from the SDMC to initiate dosing in cohort 3 with 160 mg/m

 of AVA6000 is an endorsement of the emerging safety and tolerability profile in the patients enrolled in this study to date,” Neil Bell, chief development officer of Avacta, stated in a press release at the time. “We look forward to providing additional updates as the dose-escalation phase of the trial progresses.”

AVA6000 receives orphan drug designation from the US Food and Drug Administration. News release. Avacta Group plc. September 5, 2022. Accessed September 7, 2022. 

McLaughlin F, Poplawski SE, Sanford DG, etal. Abstract 1815: AVA6000, a novel precision medicine, targeted to the tumor microenvironment via fibroblast activation protein (FAP) mediated cleavage. 

. 2022;82(suppl 12):1815. doi:10.1158/1538-7445.AM2022-1815

A study evaluating the safety, pharmacokinetics and early efficacy of AVA6000 in solid tumours. ClinicalTrials.gov. Updated April 6, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04969835

Avacta announces first patient dosed in AVA6000 pro-doxorubicin phase 1 clinical trial. News release. Avacta Group plc. August 11, 2021. Accessed September 7, 2022. 

Avacta announces second dose escalation in the phase I clinical study of AVA6000 pro-doxorubicin. News release. Avacta Group plc. June 29, 2022. Accessed September 7, 2022. 

The FDA has granted an orphan drug designation to AVA6000, a modified form of doxorubicin, for the treatment of patients with soft tissue sarcoma.

AVA6000 Granted FDA Orphan Drug Status for Soft Tissue Sarcoma

The FDA has granted an orphan drug designation to WP1122 as a potential therapeutic option for patients with glioblastoma multiforme, according to an announcement from Moleculin Biotech, Inc.

The investigative agent was developed as a 2-DG prodrug to offer a more favorable pharmacological profile. In preclinical models where tumor cells required greater glycolytic activity than normal cells, WP1122 was observed to have stronger potency than 2-DG alone.

The preclinical data reported with WP1122 illustrated the potential of the agent in this disease and supported the regulatory agency’s decision to grant it investigational new drug (IND) status.

The drug developer, Moleculin Biotech, Inc., is currently examining collaboration opportunities for the clinical development of WP1122.

“The receipt of orphan drug designation represents an important milestone for our promising WP1122 development program,” Walter Klemp, chairman and chief executive officer of Moleculin Biotech, Inc., stated in a press release. “Given the progress of our phase 1 clinical trial [NCT05195723] in healthy volunteers, the strong preclinical data supporting glioblastoma multiforme as 1 of many potential indications and the recent clearance by the FDA of IND status for WP1122 in [this disease], we believe this designation further supports the potential of WP1122 and is another step forward in further validating our deep pipeline.”

In the phase 1 study, investigators set out to explore the effects of a single dose and several days of dosing of WP1122 administered as an oral solution in healthy human volunteers.

 To be eligible for enrollment, participants needed to be between the ages of 18 years and 55 years, fully vaccinated against COVID-19 and willing to undergo testing for the virus, have a minimum body weight of at least 50 kg for men and at least 45 kg for women.

Participants needed to be healthy per physician assessment and based on a medical evaluation, which included medical history, physical examination, laboratory tests, and echocardiogram.

Those who were pregnant, breastfeeding, or intending to become pregnant were excluded, as were those with evidence of SARS-CoV-2 infection, those with respiratory disease, hypersensitivity or severe allergic reactions to vaccines or drugs, diabetes mellitus, clinically relevant hypertension, history of bleeding diathesis or coagulopathy, or cardiovascular diseases.

Each study group is comprised of 10 volunteers who are randomly assigned 4:1 to receive WP1122 or placebo. Dose escalation will take place in sequential single-dose cohorts.

In the first portion of the study, the single ascending dose portion, 8 volunteers will receive the oral investigational drug and 2 will receive placebo. Up to 40 volunteers will be enrolled to this portion of the research.

The second portion of the study, or the multiple ascending dose portion, will start after the third group in the single dosing portion of the trial has completed dosing and WP1122 is found to be safe and well tolerated. In up to 4 groups, 8 volunteers will be administered oral WP1122 and 2 will be given placebo twice daily, 12 hours apart for the duration of 7 days. Up to 40 volunteers will be enrolled to this portion of the study.

The primary outcome measures for the trial are to evaluate the safety and tolerability of escalating doses of WP1122 given as a single oral dose in sequential cohorts of healthy volunteers and to determine the maximum tolerated dose of the agent. Investigators also want to analyze the safety and tolerability of 7 days of escalating doses of the agent given every 12 hours in sequential cohorts of healthy volunteers and to identify the recommended phase 2 dose for a trial being done in patients with COVID-19.

Secondary outcome measures include examining the activity of WP1122 in the body after a single dose and multiple ascending doses; to do this, investigators will examine participants’ maximum plasma concentration.

Glioblastoma multiforme represents the most aggressive malignant primary brain tumor; this disease continues to be incurable and those diagnosed with it have a median survival of only 15 months. Glioblastoma multiforme accounts for 54% of all glioma cases and 16% of all primary brain tumors.

With orphan drug status, the clinical-stage pharmaceutical company is provided with select benefits, such as financial incentives to support clinical development. Moleculin Biotech, Inc. also has the potential for up to 7 years of market exclusivity for WP1122 in the United States if the agent is eventually approved in its designated indication.

Moleculin receives FDA orphan drug designation of WP1122 for the treatment of glioblastoma multiforme. News release. Moleculin Biotech, Inc. September 6, 2022. Accessed September 7, 2022. 

Study to assess the safety and pharmacokinetics of WP1122 in healthy volunteers. ClinicalTrials.gov. Updated May 13, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05195723

The FDA has granted an orphan drug designation to WP1122 as a potential therapeutic option for patients with glioblastoma multiforme.

FDA Grants Orphan Drug Designation to WP1122 for Glioblastoma Multiforme

The FDA has granted fast track designation to AMB-05X for the treatment of patients with tenosynovial giant cell tumor (TCGT), according to an announcement by AmMax Bio.

AMB-05X is a potent monoclonal antibody targeting CSF1R. Through its binding to the regulatory cytokines CSF1 and IL-34, CSF1R is involved in the regulation of macrophages and related cells in multiple biological processes against multiple organ systems.

“We are very pleased to receive fast track designation for AMB-05X from the FDA, which clearly reflects the significant unmet need facing thousands of patients suffering from TCGT and its numerous associated co-morbidities,” Larry Hsu, PhD, chief executive officer of AmMax Bio, stated in a press release.

“Physicians have shown tremendous enthusiasm for a locally injectable form of CSF1R inhibitor to address this localized disease in the joint,” he added. “AMB-05X is designed to be administered via an intra-articular injection at the site of the tumor to minimize the systemic exposure and the associated serious safety concerns.”

Though surgical resection is the standard of care for patients with TGCT, the risk of infections, prolonged post-operative care, and frequent relapse has created a need for a medical therapy to use alongside surgery.

AMB-05X is currently under investigation in multiple phase 2 trials for patients with TGCT. Previously reported interim data from a phase 2 trial (NCT04731675) of 5 patients showed that AMB-05X demonstrated clinical benefit, including tumor reduction per RECIST v1.1 criteria and improvements in patient-reported functional outcomes, in patients with TGCT of the knee.

 Findings also showed AMB-05X was well tolerated with no serious adverse effects (AEs) and limited non-serious grade 1/2 AEs.

The multicenter, phase 2 trial aimed to enroll approximately 12 patients with TGCT of the knee to receive 6 doses of AMB-05X over 12 weeks. Patients were required to be at least 18 years old with a confirmed diagnosis of TGCT of the knee joint and measurable disease per RECIST v1.1.

 Adequate hematologic, hepatic, and renal function was also necessary.

Patients were excluded from the trial if they received treatment with another investigational drug within 4 weeks or 5 half-lives of baseline; received prior CSF1, CSF1R, or oral TKIs; had a history of extensive knee surgery; or had metastatic TGCT.

Enrolled patients received an injection of AMB-05X once every 2 weeks for 12 weeks. The co-primary end points of the trial were treatment-emergent AEs and tumor response per RECIST v1.1. Secondary end points included tumor volume reduction, plus mean change in range of motion of the knee, patient-reported outcomes, stiffness, and pain.

Another ongoing phase 2 trial (NCT04938180) is investigating intravenous AMB-05X in patients with TGCT.

 Injections of the agent will also be evaluated in patients with TCGT in the phase 2 AMB-051-07 trial (NCT05349643) that features a long-term extension as a part of the protocol.

AmMax Bio announces AMB-05X granted FDA fast track designation for the treatment of tenosynovial giant cell tumor (TGCT). News release. AmMax Bio. September 7, 2022. Accessed September 7, 2022. 

AmMax Bio announces positive interim phase 2 results of AMB-05X for the treatment of tenosynovial giant cell tumor (TGCT). News release. AmMax Bio. October 20, 2021. Accessed September 7, 2022. 

An open-label study of intra-articular AMB-05X injections in subjects with tenosynovial giant cell tumor of the knee. ClinicalTrials.gov. Updated July 29, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04731675

A phase 2 study of intravenous AMB-05X in tenosynovial giant cell tumor patients. ClinicalTrials.gov. Updated July 29, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04938180

A phase 2 study with LTE to evaluate safety and efficacy of AMB-05X injections in subjects with TGCT. ClinicalTrials.gov. Updated April 27, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05349643

The FDA has granted fast track designation to AMB-05X for the treatment of patients with tenosynovial giant cell tumors.

FDA Grants Fast Track Designation to AMB-05X in Tenosynovial Giant Cell Tumors

Emavusertib (CA-4948) elicited antitumor activity when given as a monotherapy in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) that harbored a spliceosome or 

 mutation, according to findings from the phase 1/2 TakeAim trial (NCT04278768) presented during the 2022 EHA Congress.

The results showed a complete response (CR)/complete hematologic response (CRh) rate of 40% (n = 2/5) in patients with AML and spliceosome mutations, an objective response rate of 57% (n = 4/7) in patients with HR-MDS and spliceosome mutations, and a CR/CRh rate of 33% (n = 1/3) in patients with 

“Emavusertib demonstrated oral, single-agent anticancer activity in patients with heavily pretreated AML and HR-MDS with 

 targeted mutations [and is a] potential candidate for use in combination therapy for all patients with AML/HR-MDS, including those without a targeted mutation,” lead study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center, and coauthors, said in a presentation on the data.

Emavusertib is a selective, reversible, ATP-competitive, type 1, small molecule IRAK4 inhibitor with potential antileukemic activity. The compound is orally bioavailable and has moderate plasma binding; stability in plasma, liver microsomes, and hepatocytes; and rapid absorption and clearance. Moreover, the agent can target splicing mutations and 

 mutations and has demonstrated potential synergy with other drugs.

In preclinical models, emavusertib demonstrated a reduction in leukemic blasts as monotherapy in patient-derived xenografts and synergy when used in combination with azacitidine and venetoclax (Venclexta) in THP-1 models.

TakeAim is an open-label, single-arm, dose-escalation and -expansion study that employed a 3+3 design. On 

August 4, 2022, the FDA placed a partial clinical hold on the trial

August 30, 2022, the FDA announced that the trial could resume enrollment

 for the phase 1a portion, which is evaluating emavusertib alone.

Notably, the partial clinical hold the FDA placed on the trial in April 2022 remains in effect for the phase 1b portion of the trial, which is investigating emavusertib in combination with azacitidine or venetoclax. 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.

To be eligible for enrollment, patients had to have relapsed/refractory AML or high-risk MDS, an ECOG performance status of 2 or lower, and be at least 18 years of age.

Study treatment was administered twice daily in 28-day cycles.

The primary study objective was to determine the maximum-tolerated dose and recommended phase 2 dose of the treatment regimen. The secondary objective included the evaluation of pharmacokinetic activity and preliminary efficacy of the therapy.

The following 4 doses of emavusertib were evaluated in the escalation phase: 200 mg (n = 3), 300 mg (n = 26), 400 mg (n = 17), and 500 mg (n = 3). The dose of 300 mg was selected for the dose-expansion phase.

A total of 49 patients received treatment and all were evaluable for safety; 29 of these patients did not have targeted mutations. A total of 14 patients with a targeted mutation were evaluable for efficacy and included those with an AML spliceosome mutation (n = 6), an MDS spliceosome mutation (n = 7), and an AML 

Baseline characteristics indicated that the median patient age was 74 years (range, 32-87) and most patients were male (n = 33; 67%) and had an ECOG performance status of 1 (n = 30). The median platelet count was 30 x 103/mm3 (range, 4-275), the median absolute neutrophil count was 0.64 x 103/mm3 (range, 0-14.75), and the median number of prior therapies received was 2 (range, 1-5).

Findings from the safety analysis demonstrated that no dose-limiting toxicity occurred in the 200-mg to 400-mg dose levels in the dose-escalation phase. The rates of grade 3 or greater treatment-related adverse effects (TRAEs) in the 200-mg, 300-mg, 400-mg, and 500-mg dose levels were 33.3% (n = 1), 23.1% (n = 6), 35.3% (n = 6), and 66.7% (n = 2), respectively.

Grade 3 or higher TRAEs included increased alanine aminotransferase (200 mg, 33.3%), increased blood creatinine phosphokinase (300 mg, 3.8%), dizziness (200 mg, 33.3%), dyspnea (400 mg, 5.9%), 

 infection (400 mg, 5.9%), fatigue (400 mg, 5.9%), gastrointestinal hemorrhage (300 mg, 3.8%), hypophosphatemia (300 mg, 3.8%), hypotension (300 mg, 3.8%), increased lipase (300 mg, 7.7%), decreased platelet count (300 mg, 3.8%), presyncope (400 mg, 5.9%), rhabdomyolysis (300 mg, 3.8%; 400 mg, 11.8%; 500 mg, 33.3%), and syncope (500 mg, 33.3%).

Correlative analysis is ongoing, and trials in lymphoma and solid tumors are being evaluated.

Garcia-Manero G, Winer ES, DeAngelo DJ, et al. TakeAim Leukemia - a phase 1/2 study of the IRAK4 inhibitor emavusertib (CA-4948) monotherapy or in combination with azacitidine or venetoclax in relapsed/refractory AML or MDS. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S129

Curis announces FDA partial clinical hold for TakeAim Leukemia study of emavusertib (CA-4948). News release. Curis, Inc. April 4, 2022. Accessed September 6, 2022. 

FDA allows patient enrollment to resume in monotherapy dose escalation of emavusertib in TakeAim Leukemia study. News release. Curis, Inc. August 30, 2022. Accessed September 6, 2022. 

Emavusertib elicited antitumor activity when given as a monotherapy in patients with relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndrome that harbored a spliceosome or FLT3 mutation.

Emavusertib Is Active in Heavily Pretreated AML and High-Risk MDS With Targeted Mutations

The addition of the pre- and co-administration of nivolumab (Opdivo) with concurrent chemoradiation (CCRT) appeared to be safe and feasible in patients with locally advanced cervical carcinoma, according to data from the phase 1 GOTIC-018 trial (JMA-IIA00425).

Among those in cohort A, those who received nivolumab with CCRT and nivolumab maintenance, the complete response (CR) rate was 73.3% (n = 11), and the partial response (PR) rate was 26.7% (n = 4). Among those in cohort B, those who received induction treatment with nivolumab plus nivolumab with CCRT and nivolumab maintenance, the PR rate was 6.7% (n = 1), and the stable disease rate was 93.3% (n = 14).

“No dose-limiting toxicity [DLT] was reported during the acute phase in both cohort A and B, and no new safety signals were observed,” lead study author Akira Yabuno, of the Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan, and colleagues, wrote in a poster on the data. “Further studies assessing the safety and efficacy of pre-administration of nivolumab in patients with locally advanced cervical cancer with CCRT are needed.”

CCRT represents the current standard of care for patients with locally advanced cervical carcinoma. In those with non–small cell lung cancer, CCRT followed by immune checkpoint inhibition has significantly impacted clinical practice. In those with recurrent or metastatic cervical cancer, nivolumab has demonstrated a promising signal of activity; however, the safety and feasibility of nivolumab plus CCRT has yet to be reported in this population.

With the multicenter, prospective, open-label GOTIC-018, investigators sought to examine the safety and feasibility of pre- and co-administration of nivolumab with CCRT in those with locally advanced cervical carcinoma. The trial enrolled those with FIGO 2008 stage IB2 to IVA disease.

In cohort A, 15 patients received nivolumab at 240 mg every 2 weeks in combination with, and following, CCRT. CCRT was comprised of EBRT followed by vaginal brachytherapy with cisplatin at 40 mg/m2 once weekly for 4 or more cycles. In cohort B, 15 patients received nivolumab before, in combination with, and following CCRT. For the latter cohort, 2 cycles of nivolumab were given prior to the start of CCRT. The sample size for the trial was 30 patients.

The first 6 patients were enrolled for evaluation of DLTs in each cohort; if 0 or 1 patient experienced DLTs, an additional 9 patients were enrolled to each cohort. For cohort A, the DLT evaluation period ranged from nivolumab was administered to 28 days after the end of CCRT. For cohort B, this DLT evaluation period ranged from the start of CCRT to 28 days following CCRT completion.

Patients were enrolled to the trial from March 2019 to September 2020. The median age of patients in cohort A was 50 years (range, 26-73) vs 56 years (range, 41-71) in cohort B. Most patients in cohorts A and B had an ECOG performance status of 0 (93.3% vs 100%) and squamous cell carcinoma histology (93.3% vs 93.3%). Patients in cohorts A and B had FIGO stage IB2 (6.7% vs 6.7%, respectively), IIA (6.7% vs 0%), IIB (60.0% vs 40.0%), IIIB (26.7% vs 46.7%), or IVA (0% vs 6.7%) disease. In cohort A, 20% of patients had lymph node metastasis vs 60% of those in cohort B.

In the first 6 patients evaluable for DLTs in each cohort, no DLTs were observed. As such, the study was expanded to enroll an additional 9 patients in each cohort.

Any-grade adverse effects (AEs) were experienced by all patients. The most common grade 3 or higher AEs experienced by cohorts A and B, respectively, were anemia (13.3% vs 26.7%), leukopenia (86.7% vs 66.7%), neutropenia (60.0% vs 26.7%), thrombocytopenia (20.0% vs 0%), increased amylase (6.7% vs 0%), increased lipase (6.7% vs 6.7%), increased alanine aminotransferase (6.7% vs 6.7%), decreased appetite (13.3% vs 0%), colitis (0% vs 6.7%), and diarrhea (13.3% vs 20.0%).

No serious immune-relate toxicities were experienced in either cohort nor did any deaths occur. No patients needed to delay starting CCRT because of AEs associated with the pre-administration of nivolumab in cohort B.

In cohort A, the median number of cycles of cisplatin received was 5 (range, 3-6). Forty percent of patients required cisplatin interruption, 13.3% required dose reduction of cisplatin, and 6.7% required discontinuation of the agent. EBRT interruption was required in 13.3% of patients. The number of cycles of nivolumab was 6 (range, 1-7); this agent was interrupted in 53.3% of patients and discontinued in 6.7% of patients.

In cohort B, the median number of cisplatin cycles received was 6 (range, 4-6); this agent was interrupted in 40.0% of patients and discontinued in 6.7% of patients. The number of cycles of nivolumab received was 9 (range, 3-9); this agent was interrupted in 40.0% of patients and discontinued in 6.7% of patients.

Yabuno A, Nakamura K, Satoh T, et al. GOTIC-018: phase I open-label, multicenter study to assess the safety of pre- and co-administration of ONO-4538 (nivolumab) with concurrent chemoradiation (CCRT) in patients (pts) with locally advanced cervical carcinoma (LACvCa). 

. 2022;40(suppl 16):5529. doi:10.1200/JCO.2022.40.16_suppl.5529

The addition of the pre- and co-administration of nivolumab with concurrent chemoradiation appeared to be safe and feasible in patients with locally advanced cervical carcinoma, according to data from the phase 1 GOTIC-018 trial.

Pre- and Co-administration of Nivolumab Proves Safe in Locally Advanced Cervical Cancer Treated With CCRT

The sequential treatment of regorafenib (Stivarga) followed by nivolumab (Opdivo) was found to have an acceptable toxicity profile in patients with hepatocellular carcinoma (HCC) who progressed on and tolerated first-line sorafenib (Nexavar), according to early data from the phase 1/2a GOING trial (NCT04170556).

Data presented during the 2022 International Liver Cancer Association Conference showed that less than one-third of patients who received the regimen experienced treatment-related adverse effects (TRAEs) that were grade 3 or 4 in severity. Notably, no treatment-related deaths occurred.

“The futility analysis in cohort A based on objective response rate [is] allowed to continue recruitment,” Marco Sanduzzi-Zamparelli, MD, lead study author of the BCLC group, Liver Unit, Hospital Clinic of Barcelona, and colleagues, wrote in a poster shared at the meeting.

In the past few years, systemic treatment for patients with HCC has dramatically shifted. For example, in May 2020, the 

FDA approved the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin)

 for those with unresectable or metastatic HCC who have not previously received systemic treatment.

 Moreover, in April 2022, the FDA accepted for priority review a biologics license application seeking the approval of a 

single priming dose of tremelimumab added to regular interval durvalumab

 (Imfinzi; the STRIDE regimen) for the frontline treatment of patients with unresectable HCC.

Previous data from the phase 3 RESORCE trial (NCT01774344) showed that regorafenib (n = 379) improved median overall survival (OS) over placebo (n = 194) in patients with HCC who had progressed on sorafenib (HR, 0.63; 95% CI, 0.50-0.79; 

 The median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) vs 7.8 months (95% CI, 6.3-8.8) with placebo. Moreover, second-line nivolumab was also found to be safe and active in patients with advanced HCC, according to findings from the phase 1/2 CheckMate 040 trial (NCT01658878).

The investigator-initiated GOING trial enrolled patients with a diagnosis of HCC who had acceptable liver function, an ECOG performance status of 0 or 1, an acceptable hematologic profile, and adequate renal function.

 They needed to have developed radiological tumor progression on sorafenib treatment within 2 months of study inclusion and be eligible for regorafenib treatment per the definition utilized in RESORCE or have tolerated between 200 mg and 400 mg of sorafenib for at least 30 days. They also were required to have at least 1 measurable lesion per RECIST v1.1 criteria.

Patients could not have myocardial infarction in the last year or active ischemic heart disease, nor could they have a historically of clinically meaningful variceal bleeding within the past 3 months. Those with severe peripheral arterial disease, cardiac arrhythmia under treatment with drugs different from beta-blockers or digoxin, or those with clinically meaningful ascites, were excluded.

The trial was comprised of 2 cohorts: those with HCC who progressed on and tolerated sorafenib comprised cohort A, and those who discontinued treatment with atezolizumab/bevacizumab comprised cohort B.

Participants received regorafenib at a daily dose of 160 mg for 8 weeks. Thereafter, patients received regorafenib at the dose tolerated at week 8 in combination with nivolumab at 240 mg every 2 weeks. Treatment continued until unacceptable toxicity, symptomatic progression, patient decision, or death.

The primary aim of the trial was to measure safety in the form of AE rate, TRAE rate, and rates of AEs that resulted in treatment discontinuation or death.

A futility analysis based on radiologic response utilizing the non-binding Lan & DeMets beta-spending functions with a boundary of 

= .814 will be conducted when 32.8% of patients in cohort A had data of tumor assessment by at least week 16.

Among 30 evaluable patients in cohort A, the median age was 65 years (range, 58-72), and most patients were male (n = 26). Moreover, 53.3% of patients had cirrhosis, 15 patients had Child-Pugh A disease, and 86.7% had an ECOG performance status of 0; 76.7% of patients had BCLC stage C disease and 23.3% had BCLC stage B disease. Additionally, 36.7% of patients had extrahepatic disease, 56% had vascular invasion, and 23.3% had BCLCpC2.

The median follow-up was 3.4 months (range, 2.4-6.2). The median duration of treatment with regorafenib was 6.1 months (range, 2.6-8.9), and the median duration of treatment with nivolumab was 6.7 months (range, 4.0-9.3).

Treatment-emergent AEs were experienced by all patients; they were treatment related in 96.7% of patients. Severe treatment-emergent and -related AEs occurred in 46.7% and 33.3% of patients, respectively. Treatment-related serious AEs (TR-SAEs) associated with either agent occurred in 13.3% of patients; 10% experienced TR-SAEs associated with regorafenib alone, and 10% reported TR-SAEs linked with nivolumab alone. TRAEs resulted in treatment interruption in 26.7% of patients.

The most common TRAEs reported in over 10% of patients who received the combination were hand-foot-skin reaction (any grade, 56.6%; grade 3, 10%), asthenia (any grade, 43.3%), diarrhea (any grade, 36.7%; grade 3, 3.3%), decreased appetite (any grade, 30%), arterial hypertension (any grade, 30%; grade 3, 6.7%), hypertransaminasaemia (any grade, 30%; grade 3, 3.3%), hyperbilirubinaemia (any grade, 20%; grade 3, 3.3%), increased aspartate aminotransferase (any grade, 20%; grade 3, 3.3%), abdominal pain (any grade, 20%), dysphonia (any grade, 16.7%), and increased alanine aminotransferase (any grade, 13.3%).

The most common reason for study discontinuation was physician decision (n = 4), followed by disease progression (n = 2) and AEs (n = 1; 1 of them being a TRAE). Five patients died; 4 died from disease progression and 1 did from an AE not associated with treatment.

On July 20, 2022, a total of 48 patients were included in cohort A, and 6 patients were included in cohort B. Four evaluations by an external Data Safety Monitoring Board have been realized for cohort A, and 1 is anticipated for cohort B.

Sanduzzi-Zamparelli M, Matilla A, Lledo JL, et al. Early nivolumab addition to regorafenib in patients with hepatocellular carcinoma progressing under first line therapy (GOING trial). Interim analysis and safety profile. Presented at: 2022 International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain. Poster 102

FDA approves Genentech’s Tecentriq in combination with Avastin for people with the most common form of liver cancer. News release. Genentech. May 29, 2020. Accessed September 6, 2022. 

Tremelimumab accepted under priority review in the US for patients with unresectable liver cancer in combination with Imfinzi. News release. AstraZeneca. April 25, 2022. Accessed September 6, 2022. 

Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled phase 3 trial. 

. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9

El-Khouiery AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. 

. 2017;389(10088):2492-2502. doi:10.1016/S0140-6736(17):31046-2

Regorafenib followed by nivolumab in patients with hepatocellular carcinoma (GOING) (GOING). ClinicalTrials.gov. Updated May 11, 2022. Accessed September 6, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04170556

The sequential treatment of regorafenib followed by nivolumab was found to have an acceptable toxicity profile in patients with hepatocellular carcinoma who progressed on and tolerated first-line sorafenib, according to early data from the phase 1/2a GOING trial.

Pipeline Report: September 2022 | Articles