Gualberto, Antonio

Abstract Background: CXCL12 is a negative prognostic factor for head & neck (HNSCC) and pancreatic (PDCA) cancers, among others. Its receptor, CXCR4, is a negative prognostic factor in lymphoma/leukemia. CXCR4 signals in part through RAS species, and the expression of CXCL12 and CXCR4 appears to be itself regulated by farnesylated proteins. We provide evidence that targeting the CXCL12/CXCR4 pathway with the farnesyltransferase inhibitor tipifarnib translates to long term clinical benefit. Methods: Next generation sequencing and analyses of gene expression were conducted in tumor samples from squamous cell carcinoma, lymphoma, and acute myeloid leukemia (AML) patients treated in tipifarnib trials (studies KO-TIP-001, KO-TIP-002, CTEP20), and complemented with analyses of related tumor gene expression databases in TCGA and GEO. Results: Activating HRAS mutations in HNSCC and KRAS mutations in PDCA were mutually exclusive with CXCL12 expression, consistent with a role for RAS downstream from CXCR4. Contrary to KRAS and NRAS, HRAS is exclusively farnesylated, and treatment with tipifarnib in patients (pts) with advanced HNSCC tumors with a HRAS mutation variant allele frequency (VAF) >20% resulted in 8 partial responses (PR) in 14 pts. Two complete responses (CR), 3 PRs and 4 disease stabilizations (90% clinical benefit) were observed in 10 pts with relapsed/refractory peripheral T cell lymphoma overexpressing CXCL12. Decreases in plasma CXCL12 levels during treatment were observed. Seven CRs were observed in 11 elderly/unfit AML pts overexpressing CXCL12 in bone marrow (NRAS wt or unknown). Ex vivo treatment of bone marrow stromal cell cultures with tipifarnib decreased secretion of CXCL12. Finally, based on the reported relationship between CXCL12 expression and the suppression of pain in PDCA, we conducted a retrospective analysis of a phase 3 study of gemcitabine plus tipifarnib (GT) in advanced PDCA. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 10.2 vs 5.9 months, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 6.1 vs 6.1 months. PDCA with <7% VAF of KRAS mutation (~30% PDCA pts) overexpressed CXCL12. Conclusions: The mechanism of action of tipifarnib appears to involve targeting the CXCL12/CXCR4 pathway and demonstrates a crucial association with the tumor microenvironment and objective clinical responses. Citation Format: Antonio Gualberto, Catherine Scholz, Vishnu Mishra, Matthew R. Janes, Linda Kessler, Eric Van Cutsem, Alan L. Ho, Thomas Witzig. Mechanism of action of the farnesyltransferase inhibitor, tipifarnib, and its clinical applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT191.

Background:Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post‐translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors.Aims:Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T‐cell lymphoma (AITL) and CXCL12+ peripheral T‐cell lymphoma (PTCL) patients (pts).Methods:This Phase 2 study (NCT02464228) is a multi‐institutional, single‐arm, open‐label trial initially designed as a two‐stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/ = 18 years and a performance status of 0–2. Based on initial findings, the study was amended to include a cohort of AITL (n = 12) and PTCL (n = 12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1–21 of 28‐day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and standard of care treatment.Results:As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL‐NOS, 1 ALK‐ ALCL, 1 gamma‐delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least one treatment‐emergent adverse event (TEAE); 39 (90%) had at least 1 study drug‐related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug‐related TEAEs of Grade ≥3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n = 3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre‐treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was also retrospectively investigated in 73 pts who received standard of care therapy (AITL N = 50, PTCL NOS = 23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR = 1.8, p = 0.09) was observed using the high CXCL12 subset using the cut‐off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non‐AITL samples overexpressed CXCL12.Summary/Conclusion:Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.

Abstract Background: HRAS is a proto-oncogene that is mutated in head and neck, bladder, thyroid, and salivary gland tumors, among others. While discovered over 40 years ago, no specific therapies have yet been developed targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme requisite for HRAS activation. Over 5,000 patients (pts) have been treated with tipifarnib; although responses have been documented in several tumor indications, the mechanisms of response are still poorly understood. Tipifarnib has demonstrated robust activity in HRAS mutant patient derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and squamous non-small cell lung cancer that are resistant to standard therapies. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of mutant HRAS oncogenic activity with tipifarnib could translate to objective responses in HNSCC pts driven by the HRAS oncogene. Methods: The study was originally designed to enroll pts into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design (11+7 evaluable pts) to determine overall response rate (ORR) as the primary objective. This design has 80% power to detect a difference between 10% and 30% ORR at one-sided significance level of 0.087. Two objective responses were needed to be observed in the first stage for each cohort to proceed to stage 2. The study is considered positive if at least 4 responses are observed in one of the 2 cohorts (N=18 each, stages 1 and 2 combined). The prespecified activity goal for the first stage of accrual in Cohort 2 was met and based on data observed in the first stage of this Cohort, ongoing enrollment to the second stage of Cohort 2 was limited to HRAS mutant HNSCC. For enrollment, pts must have an HRAS mutant, locally advanced/unresectable and/or metastatic solid tumor malignancy and RECIST v1.1 measurable disease. Tipifarnib is given at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Response assessments are conducted every 8 weeks. Results: As of August 30, 2017, 28 pts have been enrolled. Tipifarnib was generally well tolerated with myelosuppression, gastrointestinal disturbances (nausea, vomiting and diarrhea) and fatigue constituting the most common adverse events (≥30% of pts, all grades). Twenty four pts are currently evaluable for efficacy: 10 in Cohort 1 and 14 in Cohort 2. Stage 1 enrollment continues in Cohort 1. The primary objective was met for Cohort 2 prior to completing full enrollment, with 4 confirmed responses observed out of 14 evaluable pts. Notably, of the 6 pts in Cohort 2 with HNSCC currently evaluable for efficacy, 4 (67%) achieved a confirmed partial response. Three of these pts remain on treatment in cycles 3, 5, and 19, and one subject discontinued at Cycle 21. Two (33%) pts had disease stabilization as best response (4 cycles, ongoing and 7 cycles). Importantly, 4 of these pts were refractory to prior therapies, including regimens containing immunotherapy (pembrolizumab, nivolumab) or cetuximab +/- chemotherapy. None of the 6 HNSCC patients experienced an objective partial response on their last prior therapy. Conclusions: These data suggest that HRAS mutant HNSCC pts may be refractory to standard therapies but can derive prolonged clinical benefit from tipifarnib treatment. Based on the encouraging activity of tipifarnib in pts with HNSCC with HRAS mutations, enrollment continues in this cohort. Citation Format: Alan Ho, Nicole Chau, Deborah J. Wong, Maria E. Cabanillas, Jessica Bauman, Marcia S. Brose, Keith Bible, Valentina Boni, Irene Brana, Charles Ferte, Caroline Even, Francis Burrows, Linda Kessler, Vishnu Mishra, Kelly Magnuson, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A10.

Purpose We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC). Patients and Methods Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study. Results A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. Conclusion These data suggest that PCI20 is safe and effective in patients with NSCLC.

PurposeA phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.Patients and MethodsAfter informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.ResultsNo CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.ConclusionThese data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.