The CCR5 antagonist leronlimab (PRO140) plus carboplatin was shown to result in a 72% decrease in cancer-associated macrophage-like cells (CAMLs), which was linked with an approximate 450% increase in overall survival (OS) in 30 patients with metastatic triple-negative breast cancer (mTNBC), according to preliminary data from a 12-month analysis of phase 1b/2 trials.

The decreases in CAMLs were reported after just 4 doses of leronlimab and occurred about 30 days following induction with the agent. The decrease in CAMLs was also found to be associated with an approximate 300% increase in mean progression-free survival (PFS) in this population.

Investigators also noted that high CCR5 observed in tumor tissue biopsies could help to stratify patients who are likely to experience disease progression on leronlimab. Conversely, reductions in CAMLs and circulating tumor cells (CTCs) may be related to slower progression and lower mortality. Additionally, CAMLs may help to identify patients who will respond to leronlimab.

“While these are only interim results at the 12-month point, our ability to rapidly monitor and identify patients who appear to respond to leronlimab using a single tube of blood is quite an encouraging finding,” Daniel Adams, director of Clinical Research & Development at Creatv MicroTech, Inc., stated in a press release. “The fact that greater than 70% of patients saw positive changes in CTCs after a single dose of leronlimab was made even more informative by their dramatic increases in both PFS and OS. The fact that a large group of patients taking leronlimab had a median PFS of approximately 6 months is well beyond that experienced with current treatment options available to those women, who typically have a median PFS of approximately 2 months.”

An investigational humanized IgG4 monoclonal antibody, leronlimab blocks CCR5 which is a cellular receptor that seems to play several roles with implications in HIV infection, tumor metastases, and signaling.

FDA granted a fast track designation to leronlimab

 for use in combination with carboplatin in the treatment of patients with CCR5-positive, metastatic TNBC.

 The agent has also received fast track status for use in combination with highly-active antiretroviral therapy in patients with HIV infections.

The CCR5 receptor may play a role in modulating immune-cell trafficking to inflammation sites; thus, the receptor could be crucial in the development of acute graft-versus-host disease and other inflammatory conditions. Blocking CCR5 with a chemical inhibitor could result in a reduction in the clinical impact of acute GVHD without interfering with the engraftment of transplanted bone marrow stem cells.

Prior research has indicated that CCR5 is involved in tumor invasion and metastasis and that increased expression of this marker could be indicative of disease status in many cancers. Additional findings have revealed that CCR5-blocking agents can stop tumor metastases in laboratory and preclinical models of aggressive breast cancer and prostate cancer. The agent has been shown to reduce breast cancer metastasis by over 97% in a murine xenograft model.

In a phase 2 basket trial (NCT04504942), leronlimab is under investigation in 30 patients with CCR5-positive locally advanced or metastatic solid tumors.

 To participate, patients need to have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumors who have progressed on standard therapy, are receiving a standard anticancer treatment, are unable to receive standard therapy, or for whom standard treatment is not available.

Patients needed to have CCR5 positivity per immunohistochemistry, measurable disease per RECIST v1.1 criteria, be at least 18 years of age, an ECOG performance status of 0 or 1, a life expectancy of at least 6 months, and acceptable organ and bone marrow function within 28 days before registration, along with other criteria.

In the trial, study participants will receive the agent via a subcutaneous administration at a weekly dose of 525 mg until disease progression or intolerable toxicity. Patients will be permitted to receive or to continue standard chemotherapy or radiotherapy per the dosing schedule included on the package insert.

The primary end points of the trial include the number, frequency, and severity of adverse effects, the incidence of abnormal laboratory test results, and changes in ECOG performance status from baseline to subsequently scheduled visits. Secondary end points included PFS, ORR, clinical benefit rate, time to new metastases, changes from baseline in CTCs, and OS.

The agent is also under exploration for use in patients with HIV and those with COVID-19.

CytoDyn announces preliminary results from 30 mTNBC patients treated with leronlimab. Decreases in CAMLs after 4 doses of leronlimab were indentified in over 70% of patients and were associated with a 450% significant increase in overall survival at 12-month analysis. News release. CytoDyn Inc. July 19, 2021. Accessed July 20, 2021. 

FDA grants CytoDyn fast track designation for leronlimab (PRO 140) in metastatic triple-negative breast cancer, an unmet medical need. CytoDyn Inc. May 7, 2019. Accessed July 20, 2021. 

Basket study of leronlimab (PRO 140) in patients with CCR5+ locally advanced or metastatic solid tumors. ClinicalTrials.gov. Updated August 7, 2020. Accessed July 20, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04504942

Articles

The CCR5 antagonist leronlimab plus carboplatin was shown to result in a 72% decrease in cancer-associated macrophage-like cells, which was linked with an approximate 450% increase in overall survival in 30 patients with metastatic triple-negative breast cancer.

Leronlimab Plus Carboplatin Showcases Early Signs of OS Benefit in Metastatic TNBC

The combination of galinpepimut-S and pembrolizumab (Keytruda) has demonstrated promising clinical immunobiological activity in patients with Wilms Tumor 1 (WT1)–positive, relapsed or refractory, platinum-resistant advanced metastatic ovarian cancer, according to results from an ad-hoc analysis of a phase 1/2 trial.

At a median follow-up of 15.4 weeks, the combination yielded a disease control rate of 63.6% in a cohort of 11 patients. Moreover, the median progression-free survival (PFS) was 11.8 weeks with this approach, and the landmark 6-month PFS rate by log-rank analysis was 33%. Additionally, the rate of WT1 ovarian tumor positivity among patients was 63.6%. The median overall survival (OS) has not yet been reached.

“Considering the overall poor prognosis in this particular clinical setting and based on the observed median PFS, OS, and DCR in this study, combining galinpepimut-S with the PD-1 inhibitor pembrolizumab appears to be clinically promising as compared with bevacizumab [Avastin]-free salvage chemotherapy regimens and without the toxicity burden associated with the latter,” Angelos Stergiou, MD, ScD, the president and CEO of SELLAS, stated in a press release.

Patients enrolled to the study received treatment with at least 3 doses of galinpepimut-S, the last of which was combined with pembrolizumab. The median age of the participants was 63 years; 66.7% were refractory to or had their second-line therapies fail; and 33.3% of patients had a third-line or later therapy fail. Additionally, 100% of patients were resistant to the standard-of-care platinum-based therapy.

In 3 patients, CD8-positive and CD4-positive T-lymphocytes were isolated from peripheral blood mononuclear cells. In these patients, samples were collected at baseline, as well as 18 weeks after treatment initiation with the investigational agent. Then, the T cells were assayed ex vivo for immune responses against the 4 peptides that comprise galinpepimut-S through intracellular cytokine staining with fluorescence-activated single cell sorting.

The following 5 cytokine channels were utilized for the assessment: interferon-g, TNF-a, interleukin-2, CD107a, and MIP-1b. The peptide re-challenge incubation period was 1 week. At 18 weeks vs pre-vaccination baseline, the assay showed an increase in WT1-specific T-lymphocyte frequencies in peripheral blood at an average of +242% (range, +104% to +386% across 5 cytokines) for CD8-positive cells, and +80.5% (range, +1% to +174%) for CD4-positive cells. Moreover, 66% of patients (n = 2/3) showed evidence of polyfunctional T-cell activation.

All patients in the cohort are still alive and 45.5% of patients (n = 5) are still receiving treatment.

The toxicity profile observed with the combination of galinpepimut-S and pembrolizumab was comparable to the data seen with pembrolizumab alone. However, low-grade, temporary local reactions at the galinpepimut-S injection site were reported, and consistent with prior studies examining the agent.

Enrollment for the study is ongoing, with a target of 20 evaluable patients.

“Based on these early data, it is encouraging to see the induction of WT1-specific T-cell immune responses with the administration of GPS in combination with pembrolizumab with a validated complex ex-vivo immune response assay on peripheral blood from patients with platinum-refractory metastatic ovarian cancer who had undergone numerous prior therapies,” Jeffrey S. Weber, MD, PhD, the deputy director of the Perlmutter Cancer Center at NYU Langone Health, and chair of SELLAS’ Scientific Advisory Board, added in the press release.

SELLAS reports promising updated clinical data and initial immune response profiles from ongoing phase 1/2 study of galinpepimut-S (GPS) combined with Keytruda for treating WT1+ advanced ovarian cancer. News release. SELLAS Life Sciences Group, Inc. June 30, 2021. Accessed July 7, 2021. https://bit.ly/3jUtsbm

The combination of galinpepimut-S and pembrolizumab has demonstrated promising clinical immunobiological activity in patients with Wilms Tumor 1–positive, relapsed or refractory, platinum-resistant advanced metastatic ovarian cancer, according to results from an ad-hoc analysis of a phase 1/2 trial. 

Galinpepimut-S Plus Pembrolizumab Shows Early Activity in Advanced Ovarian Cancer 

The investigational RNA interference (RNAi) therapy, ARO-HIF2, was shown to have encouraging signals of activity with favorable tolerability in heavily pretreated patients with advanced clear cell renal cell carcinoma (RCC), according to data from the phase 1b AROHIF21001 (NCT04169711).

Results showed that 9 of 17 patients who received treatment had evaluable tumor samples. Of these patients, 7 showcased reductions in HIF2α, as measured by immunohistochemistry H-score. Reductions ranged from -9% to -82%, translating to a mean reduction of -48%.

Additionally, 1 patient in cohort 2 (n = 10) experienced a partial response to treatment and tumor shrinkage of approximately 65%. Five patients experienced a best response of stable disease. Four patients in cohort 2 with disease stability continue to receive the investigational agent; the treatment duration in these patients fall between 12 weeks and 24 weeks.

ARO-HIF2 has been found to be well tolerated, overall, when administered at weekly doses of up to 525 mg. Notably, no patients have experienced treatment-related anemia.

“The AROHIF21001 phase 1b study is designed to evaluate safety as well as preliminary pharmacodynamics and efficacy in an advanced clear cell RCC patient population,” James Hamilton, MD, MBA, senior vice president of discovery and translational medicine at Arrowhead Pharmaceuticals, Inc., stated in a press release. “We believe that in the first 2 dose cohorts investigational ARO-HIF2 is showing clear signs of meaningful target engagement and some potentially early signs of efficacy in at least 1 patient. This is an encouraging start for a study.”

ARO-HIF2 was designed to inhibit the production of HIF-2α, which is known to be associated with disease progression and metastasis in clear cell RCC.

 HIF-2α represents an attractive target for intervention as more than 90% of these tumors express a mutant form of Von Hippel-Landau protein that cannot degrade this marker; this results in its accumulation during tumor hypoxia and encourages tumor growth. The investigational agent utilizes a new extra-hepatic delivery vehicle.

In the dose-finding, phase 1b trial, investigators set out to examine the safety of ARO-HIF2 in patients with advanced clear cell RCC and to identify the recommended phase 2 dose of the agent.

To be eligible for enrollment, patients needed to have histologically confirmed locally advanced or metastatic clear cell RCC that had progressed during or after at least 2 previous regimens which must have included a VEGF-targeted therapy and checkpoint inhibitor therapy.

 Patients also needed to have an ECOG performance status of 0 or 1, an estimated lifte expectancy of longer than 3 months, and acceptable organ function at the time of screening.

Patients were excluded if they had a history of untreated brain metastases or leptomeningeal disease or spinal cord compression, were unable to recover from reversible effects of prior treatment, if they received systemic therapy or radiation within 2 weeks before the first study dose, or if they had a history of solid organ or stem cell transplantation.

Secondary objectives of the trial included the examination of pharmacokinetics and preliminary efficacy in accordance with RECIST v1.1 criteria. Exploratory objectives of the research include the assessment of post-dose tumoral expression of HIF genes in response to treatment with the agent, change in tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, and the examination of serum biomarkers of agent activity. Investigators also set out to evaluate the correlation of disease-related gene expression to the activity of the agent, and to assess plasma and urine metabolites.

Study participants received intravenous injections of the agent at a weekly dose of 225 mg if they were in cohort 1 (n = 7) or 525 mg if they were in cohort 2 (n = 10). The study has progressed to examining a weekly dose of 1050 mg, which will be examined in a third cohort.

“Tumors typically have a high level of heterogeneity and the patients in AROHIF21001 have advanced clear cell RCC and have failed multiple lines of treatment, including checkpoint inhibitors and anti-VEGF regimens, so these early results in a heavily pretreated population are encouraging for investigational ARO-HIF2 and our tumor-targeted platform broadly,” Hamilton added. “ARO-HIF2 has been generally well-tolerated, and we look forward to continued dose escalation.”

Arrowhead Pharmaceuticals, Inc. is currently enrolling the third planned patient cohort of the trial and has shared plans to present additional findings at an upcoming medical meeting.

Arrowhead announces positive interim results from phase 1b study of ARO-HIF2 for treatment of clear cell renal cell carcinoma. News release. Arrowhead Pharmaceuticals, Inc. July 6, 2021. Accessed July 7, 2021. 

Pipeline: novel drugs to treat intractable diseases. Arrowhead Pharmaceuticals, Inc. Accessed July 7, 2021. 

Study of ARO-HIF2 in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated April 19, 2021. Accessed July 7, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04169711

The investigational RNA interference therapy, ARO-HIF2, was shown to have encouraging signals of activity with favorable tolerability in heavily pretreated patients with advanced clear cell renal cell carcinoma.

Pipeline Report: July 2021

Articles

Leronlimab Plus Carboplatin Showcases Early Signs of OS Benefit in Metastatic TNBC

Galinpepimut-S Plus Pembrolizumab Shows Early Activity in Advanced Ovarian Cancer