On April 8, 2022 Clovis Oncology, Inc. (NASDAQ: CLVS), reported that two abstracts featuring non-clinical data from studies evaluating FAP-2286 and Rubraca and a Trial-in-Progress poster detailing the Phase 1 portion of the LuMIERE study will be presented at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, being held April 8-13, 2022, in New Orleans (Press release, Clovis Oncology, APR 8, 2022, View Source [SID1234611646]).
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In a new non-clinical data analysis, FAP-2286 demonstrated potent affinity for human fibroblast activation protein (FAP) by biochemical and cell-based assays. Additionally, lutetium-177 (177Lu)-FAP-2286 showed longer tumor retention, resulting in greater tumor inhibition as compared to lutetium-177 (177Lu)-FAPI-46, a FAP-targeted radiotracer developed for therapeutic applications at the University of Heidelberg, Germany.
FAP-2286 is the first peptide-targeted radionuclide therapy (PTRT) and imaging agent targeting FAP to enter clinical development and the lead candidate in Clovis Oncology’s targeted radionuclide therapy (TRT) development program.
Approximately 50 patients will be enrolled in the Phase 1 portion of the multicenter, open-label LuMIERE trial, which is currently enrolling patients with advanced solid tumors (NCT04939610). The Phase 1 portion of the study is evaluating the safety of the investigational therapeutic agent 177Lu-FAP-2286 and will identify the recommended Phase 2 dose and schedule. The safety and tumor uptake of the imaging agent gallium-68 (68Ga)-FAP-2286 is also being evaluated. Once the Phase 2 therapeutic dose is determined, Phase 2 expansion cohorts in multiple tumor types are planned for later in 2022.
Separately, non-clinical data evaluating Rubraca efficacy in a panel of tumors with deleterious alterations in a core group of non-BRCA HRR genes showed responses similar to the efficacy observed in BRCA1/2-altered models. The goal of the studies was to investigate the in vitro and in vivo synthetic lethality activity of Rubraca in multiple cancer cell types and tumors harboring genetic or epigenetic alterations in non-BRCA HRR genes.
"The non-clinical data presented at AACR (Free AACR Whitepaper) further show the potential of FAP-2286, our first targeted radiotherapy candidate, as a therapeutic and imaging agent and we look forward to sharing initial clinical data from the Phase 1 portion of the LuMIERE study of FAP-2286 later this year," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We also remain committed to a greater understanding how patients with tumors associated with different genetic alterations may benefit from treatment with Rubraca."
The following Clovis-sponsored posters and supplemental information will be available as of Friday, April 8 at 1:00 p.m. CDT at View Source
FAP-2286
Abstract #3317: Comparative biodistribution and radiotherapeutic efficacy of the fibroblast activation protein (FAP)-targeting agents FAP-2286 and FAPI-46
Lead Author: Dirk Zboralski, Ph.D., 3B Pharmaceuticals GmbH, Berlin, Germany
Poster Session: Preclinical Radiotherapeutics
Date/Time: April 12, 1:30 – 5:00 p.m. CDT
Key Takeaways: FAP-2286 demonstrated potent affinity for human FAP by biochemical and cell-based assays. 177Lu-FAP-2286 showed longer tumor retention, resulting in greater tumor inhibition as compared to 177Lu-FAPI-46. The prolonged tumor retention of FAP-2286 correlated with a higher intracellular accumulation.
Abstract #CT251: LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors
Lead Author: Jonathan McConathy, M.D., Ph.D., University of Alabama School of Medicine, Birmingham, AL.
Poster Session: Phase I Trials in Progress 2
Date/Time: April 13, 9:00 a.m. – 12:30 p.m. CDT
Key Takeaways: Peptide-targeted radionuclide therapy directed toward FAP with the agent FAP-2286 has demonstrated antitumor activity in preclinical studies. LuMIERE (NCT04939610) is an ongoing phase 1/2, multicenter, open-label study evaluating safety and tolerability, pharmacokinetics (PK), dosimetry, and preliminary activity of the therapeutic agent 177Lu-FAP-2286 in patients with a FAP-expressing solid tumor. Safety and tumor uptake of the imaging agent 68Ga-FAP-2286 are also being evaluated.
For more information about FAP-2286, Targeted Radionuclide Therapy (TRT), or Clovis’ TRT development program, click here.
Rubraca
Abstract #1260: Nonclinical evaluation of rucaparib in tumors with mutations in non-BRCA1/2 homologous recombination repair (HRR) genes
Lead Author: Liliane Robillard, M.S., Clovis Oncology, Inc., Boulder, CO.
Poster Session: Biomarkers Predictive of Therapeutic Benefit 2
Date/Time: April 11, 9:00 a.m. – 12:30 p.m. CDT
Key Takeaways: In vitro small interfering ribonucleic acid (siRNA) knockdown of a subset of HRR genes showed synthetic lethality with rucaparib treatment in ovarian and prostate cancer cell lines. Rucaparib efficacy observed in patient-derived tumor xenograft (PDX) models with deleterious alterations in a core group of non-BRCA HRR genes was similar to the efficacy observed in
BRCA1/2
-altered models across different solid tumors, with enhanced sensitivity in tumors with biallelic alterations.
About FAP-2286
FAP-2286 is a clinical candidate under investigation as a peptide-targeted radionuclide therapy (PTRT) and imaging agent targeting fibroblast activation protein (FAP). FAP-2286 consists of two functional elements; a targeting peptide that binds to FAP and a site that can be used to attach radioactive isotopes for imaging and therapeutic use. High FAP expression has been shown in pancreatic ductal adenocarcinoma, salivary gland, mesothelioma, colon, bladder, sarcoma, squamous non–small cell lung, squamous head and neck cancers, and cancer of unknown primary. High FAP expression was detected in both primary and metastatic tumor samples and was independent of tumor stage or grade. Clovis holds US and global rights for FAP-2286 excluding Europe, Russia, Turkey, and Israel.
FAP-2286 is an unlicensed medical product.
About Targeted Radionuclide Therapy
Targeted radionuclide therapy is an emerging class of cancer therapeutics, which seeks to deliver radiation directly to the tumor while minimizing delivery of radiation to normal tissue. Targeted radionuclides are created by linking radioactive isotopes, also known as radionuclides, to targeting molecules (e.g., peptides, antibodies, small molecules) that can bind specifically to tumor cells or other cells in the tumor environment. Based on the radioactive isotope selected, the resulting agent can be used to image and/or treat certain types of cancer. Agents that can be adapted for both therapeutic and imaging use are known as "theranostics." Clovis, together with licensing partner 3B Pharmaceuticals, is developing a pipeline of novel, targeted radiotherapies for cancer treatment and imaging, including its lead candidate, FAP-2286, an investigational peptide-targeted radionuclide therapeutic (PTRT) and imaging agent, as well as three additional discovery-stage compounds.
About the LuMIERE Clinical Study
LuMIERE is a Phase 1/2 study evaluating FAP-2286 as a peptide-targeted radionuclide therapy (PTRT) targeting fibroblast activation protein, or FAP, in patients with advanced solid tumors. The Phase 1 portion of the LuMIERE study is evaluating the safety of the investigational therapeutic agent and will identify the recommended Phase 2 dose and schedule of lutetium-177 labeled FAP-2286 (177Lu-FAP-2286). FAP-2286 labeled with gallium-68 (68Ga-FAP-2286) will be utilized as an investigational imaging agent to identify patients with FAP-positive tumors appropriate for treatment with the therapeutic agent. Once the Phase 2 dose is determined, Phase 2 expansion cohorts are planned in multiple tumor types.
About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.
Rubraca is an unlicensed medical product outside of the US and Europe
Rubraca US FDA Approved Indications
Ovarian Cancer
Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Rubraca is indicated for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.
Prostate Cancer
Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents.
Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 months following the last dose of Rubraca.
Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).
Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).
Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.
Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.