No dose-limiting toxicities (DLTs) have been reported in the first cohort of patients with relapsed clear cell sarcoma who received the combination of devimistat (CPI-613) and hydroxychloroquine in the dose-escalation portion of the ongoing phase 1/2 APOLLO 613 trial (NCT04593758).

Devimistat was developed to target the enzymes that are involved in cancer cell energy metabolism and are located within the mitochondria of cancer cells. Specifically, the agent targets the TCA cycle, which is a critical process for tumor cell multiplication and survival or selectively in cancer cells.

The agent significantly increases cellular stress and the sensitivity of cancer cells to a wide range of chemotherapy drugs. That synergy allows for the agent to potentially be combined with other drugs at lower doses to boost efficacy and reduce adverse effects.

“The success of our first cohort of dose escalation increases our optimism that devimistat may help address the gaps for efficacious treatment for relapsed clear cell sarcoma,” Sanjeev Luther, president and chief executive officer of Rafael Pharmaceuticals, stated in a press release. “There is a significant unmet need in treatments for clear cell sarcoma and other rare cancers, and as such, patients and physicians in the rare disease community are incredibly hopeful of devimistat’s capabilities.”

The trial enrolled patients between the ages of 11 years and 75 years who have a Karnofsky performance status of greater than 60 and ECOG performance status ranging from 0 to 2, as well as acceptable liver and neurologic function.

The phase 1 portion of the trial includes those with relapsed or refractory clear cell sarcoma and other fusion-positive relapsed or refractory sarcoma. Those with Ewing sarcoma were also permitted. The phase 2 portion will enroll patients with relapsed or refractory clear cell sarcoma.

If patients received other chemotherapy within 1 week of study therapy initiation, if they have hypersensitivity to any of the components of either study agent, any other medical or psychological condition, or no marked baseline prolongation of QT/QTc interval, they were excluded. Other exclusion criteria include having potentially curative anticancer therapy available or being pregnant or breastfeeding.

Participants received hydroxychloroquine at a dose of 2.5 mg/kg followed by 1000 mg/m2 of devimistat. Twelve hours after the first dose, a daily dose of 2.5 mg/kg of hydroxychloroquine was given on days 1 through 5 of each 28-day cycle.

The primary outcome measures were maximum tolerated dose, toxicity, and overall response rate. Secondary outcome measures include duration of response, progression-free survival, and overall survival.

Additional trial sites will be added at Seattle Children’s and Atrium Health Wake Forest Baptist. Existing sites enrolling patients include City of Hope, Cleveland Clinic Children’s, University of Michigan’s Rogel Cancer Center, and Vanderbilt University Medical Center.

“Enrolling patients into our second cohort of dose escalation so soon after establishing safety in the first cohort demonstrates the dire need and demand for effective treatments for rare sarcomas,” Rashmi Chugh, MD, co-principal investigator on the trial and clinical professor at the University of Michigan Health, added in the release. “We are hopeful that devimistat will produce favorable outcomes for those suffering from relapsed clear cell sarcoma.”

In November 2021, the first patient was enrolled to the trial.

Rafael Pharmaceuticals announces successful completion of dose escalation with no dose-limiting toxicity (DLT) in first cohort of APOLLO 613 phase 1/2 clinical trial of CPI-613 (devimistat) in patients with relapsed clear cell sarcoma. News release. Rafael Pharmaceuticals, Inc.; January 6, 2022. Accessed January 7, 2022. 

To evaluate maximum tolerated dose (MTD), safety and efficacy of CPI-613 (devimistat) plus hydroxychloroquine in patients with relapsed or refractory clear cell sarcoma of soft tissue. ClinicalTrials.gov. Updated September 28, 2021. Accessed January 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04593758

Rafael Pharmaceutical announces first patient enrolled in APOLLO 613 phase 1/2 clinical trial of CPI-613 (devimistat) in patents with relapsed clear cell sarcoma. News release. Rafael Pharmaceuticals, Inc.; November 11, 2021. Accessed January 7, 2022. 

Articles

No dose-limiting toxicities have been reported in the first cohort of patients with relapsed clear cell sarcoma who received the combination of devimistat and hydroxychloroquine in the dose-escalation portion of the ongoing phase 1/2 APOLLO 613 trial.

Devimistat Plus Hydroxychloroquine Shows Early Promise in Relapsed Clear Cell Sarcoma

CA-4948 monotherapy was found to have preliminary activity with acceptable safety and tolerability in patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to updated data from an ongoing phase 1/2 trial (NCT04278768).

Among 5 patients with U2AF1 or SF3B1 spliceosome-mutated, relapsed/refractory AML, the agent was found to produce a complete response (CR) or complete response with partial hematologic recovery (CRh) rate of 40%. Notably, both patients who achieved CR/CRh have been on the study for longer than 6 months and achieved minimal residual disease negativity status. Moreover, 3 patients with elevated blast counts experienced a 50% or higher tumor burden reduction in their counts.

In 7 patients with U2AF1 or SF3B1 spliceosome-mutated, relapsed/refractory MDS, CA-4948 was found to elicit an objective response rate of 57%. One of these patients who achieved a marrow CR went on to undergo stem cell transplant following cycle 1 of treatment. Four patients experienced a 50% or greater reduction in their blast counts.

-mutated, relapsed/refractory AML, the agent elicited a CR rate of 33%, with 2 patients showcasing eradication of the mutation after treatment underscoring the agent’s disease-modifying potential. In this subset, 2 patients with elevated blast counts experienced a 50% or higher reduction in their counts.

“These data continue to build on what we believe to be a compelling profile for CA-4948, showing its activity as a monotherapy in a targeted population of patients living with relapsed/refractory AML/MDS, for whom prior lines of therapy have been unsuccessful,” James Dentzer, president and chief executive officer of Curis, Inc., stated in a press release. “We are especially pleased that these results demonstrate both a favorable safety profile and improved anticancer activity compared with standard-of-care therapies for these patients.”

The open-label, single-arm, dose-escalation trial used a 3+3 design to evaluate the safety and activity of CA-4948. A total of 22 patients had been enrolled; this included 11 patients with high-risk MDS and 11 patients with AML. Participants were administered CA-4948 at 1 of the following dose levels, twice daily: 200 mg, 300 mg, 400 mg, and 500 mg.

The primary objective of the trial was to identify the maximum tolerated dose and the recommended phase 2 dose (RP2D) of the agent based on safety and tolerability, dose-limiting toxicities, biologic activity, and pharmacokinetic and pharmacodynamic activity.

Prior data from the trial were shared during the 2021 EHA Congress and showcased the potential of CA-4948 in these patient populations whose disease is characterized by spliceosome or 

“Today’s clinical data update provides an expanded data set for this genetically-defined patient population and further support the rationale for seeking a discussion with FDA in the first half of 2022 to discuss the potential for a rapid registrational path forward for CA-4948 as a monotherapy in genetically-defined patient populations,” according to Curis, Inc.

As of December 16, 2021, a total of 49 patients with relapsed/refractory AML or MDS had received treatment with CA-4948 at any of the following dose levels: 200 mg, 300 mg, 400 mg, and 500 mg.

Regarding safety, the agent was found to be well tolerated across several dose levels, including the RP2D of 300 mg twice daily. The treatment-related adverse effects reported with CA-4948 were noted to be manageable and reversible. No dose-limiting myelosuppression was reported, nor were any cumulative toxicities observed. Notably, no grade 4 or 5 treatment-related toxicities were experienced.

Enrollment to the phase 1 trial is ongoing. Additional data are anticipated to be shared at a medical conference in 2022.

Curis announces updated data with additional encouraging clinical activity in phase 1/2 study of CA-4948 monotherapy in targeted patients with relapsed or refractory AML and MDS; and initial clinical data from phase 1 study of CI-8993 in patients with relapsed or refractory solid tumors. News release. Curis, Inc.; January 6, 2022. Accessed January 7, 2022. 

Curis announces positive updated data from ongoing phase 1/2 study of CA-4948 monotherapy in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes. News release. Curis, Inc.; June 11, 2021. Accessed January 7, 2022. 

CA-4948 monotherapy was found to have preliminary activity with acceptable safety and tolerability in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes, according to updated data from an ongoing phase 1/2 trial.

CA-4948 Shows Early Activity, Tolerability in Relapsed/Refractory AML and High-Risk MDS

Mirati Therapeutics and Verastem Oncology have entered a nonexclusive clinical collaboration to evaluate the combination of adagrasib plus VS-6766 for patients with non–small cell lung cancer (NSCLC) harboring a 

G12C mutation who have progressed on a KRAS G12C inhibitor in a phase 1/2 trial.

The primary objective of the multicenter single-arm trial is to determine the maximum tolerated dose and the recommended phase 2 dose of the combination. Safety, tolerability, and efficacy will also be evaluated. Under the terms of the agreement, Verastem Oncology and Mirati Therapeutics will have joint oversight of the study.

“Mirati [Therapeutics] and Verastem Oncology share the commitment to scientifically driven design of clinical trials for patients with cancer,” said Jonathan Pachter, PhD, chief scientific officer of Verastem Oncology in an email to 

. “The importance of combination strategies for [patients with] 

-mutant NSCLC, the compelling preclinical combination data, and the favorable clinical safety profiles of VS-6766 and adagrasib, make this a compelling combination to evaluate in this patient population.”

Adagrasib, an investigational KRAS G12C inhibitor developed by Mirati Therapeutics, is being evaluated in the phase 1/2 KRYSTAL-1 trial (NCT03785249) as a single-agent treatment for patients with NSCLC harboring a 

 G12Cmutation previously treated with chemotherapy and a PD-L1 inhibitor. As of August 30, 2020, 79 patients were treated with 600 mg of adagrasib twice daily.

Among 51 patients evaluable for clinical activity, 45% experienced a partial response (PR) and 26 patients achieved stable disease. Commonly reported treatment-emergent adverse events included nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%).

“Adagrasib covalently and irreversibly binds to and locks KRAS G12C in its inactive, GDP-bound state,” James Christensen, PhD, chief scientific officer of Mirati Therapeutics, Inc, wrote in an email. “It has a differentiated molecular profile, including an approximately 24-hour half-life, to enable near-complete inhibition of mutant 

G12C throughout the entire dosing interval as well as extensive tissue distribution. These attributes have the potential to lead to greater tumor shrinkage and durable clinical activity.”

VS-6766, a RAF/MEK inhibitor developed by Verastem Oncology, has previously shown activity with defactinib, a FAK inhibitor, in patients with NSCLC harboring a 

 mutation in a cohort of 10 patients in the phase 1/2 FRAME basket trial (NCT03875820).

Preliminary results showed that 1 patient had a partial response and 8 patients achieved disease control with 70% of patients on treatment for at least 12 weeks, and 30% on treatment at 24 weeks.

“In contrast to MEK inhibitors, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK,” Patcher said. “This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors and with its intermittent dosing schedule, it has a favorable safety profile.”

The combination of adagrasib and VS-6766 blocks 3 sequential nodes in the RAS pathway: 

. Acquired resistance to KRAS G12C inhibitors occurs in patients primarily through additional mutations in the RAS pathway, many of which may be addressed with a downstream inhibitor such as VS-6766, Patcher said. Preclinical data have shown that the combination has resulted in a deeper blockade of ERK pathway signaling pathway, according to Patcher, leading to greater antitumor efficacy relative to either agent alone.

 mutations occur in approximately 25% of patients with NSCLC adenocarcinoma,” Patcher said. “Two of the most common types of 

 mutations are G12C, present in approximately 14% of patients with NSCLC adenocarcinoma, and G12V, occurring in approximately 7% of [patients with] NSCLC. Even with the approval of sotorasib [Lumakras] and clinical results with adagrasib, there remains a high unmet need in terms of both response rate and durability of response in the second line setting.”

Mirati Therapeutics and Verastem Oncology partner to evaluate adagrasib in combination with vs-6766 in krasg12c-mutant non-small cell lung cancer. News release. Mirati Therapeutics. November 22, 2021. Accessed December 3, 2021. prn.to/3qgsPuo

Riely G, Ou SI, Rybkin I, et al. KRYSTAL-1: activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non-small- cell lung cancer (NSCLC) harboring KRASG12C mutation. 

. 2021;16(suppl 4):S748-S802. doi:10.1016/S1556-0864(21)01941-9

Verastem Oncology announces preliminary data from investigator-initiated study highlighting clinical activity of RAF/ MEK and FAK combination in KRAS Mutant tumors presented at the American Association for Cancer Research 2020 Virtual Annual Meeting I. News release. Verastem, Inc. April 27, 202

Mirati Therapeutics and Verastem Oncology have entered a nonexclusive clinical collaboration to evaluate the combination of adagrasib plus VS-6766 for patients with non–small cell lung cancer harboring a KRAS G12C mutation who have progressed on a KRAS G12C inhibitor in a phase 1/2 trial.

Pipeline Report: January 2022

Articles

Devimistat Plus Hydroxychloroquine Shows Early Promise in Relapsed Clear Cell Sarcoma

CA-4948 Shows Early Activity, Tolerability in Relapsed/Refractory AML and High-Risk MDS