Mansoor N. Saleh

Phase I trial of an anti-CD19 deglycosylated ricin A chain immunotoxin in non-Hodgkin's lymphoma : Effect of an intensive schedule of administration

In a phase I trial, eight patients with non-Hodgkins B-cell lym-phoma received mouse IgG1k monoclonal antibody HD37 specific for CD19 conjugated to deglycosylated ricin A chain (dgA) administered in four doses at 4-h intervals with total doses ranging from 4− 12 mg/m2. This schedule generated serum levels of immunotoxin which were sustained over 36 h. The plasma half-life of HD37-dgA was 17 ± 4 (SD) h. The HD37-dgA conjugate was stable in vivo as demonstrated by serum levels of HD37-dgA conjugate comparable to those of total HD37 antibody. Peak serum levels attained after the fourth dose ranged from 0.36 to 5.63 μg/ml. Two of seven evaluable patients developed modest human anti-immunotoxin antibody responses. Toxicity in patients 1–7 consisted of dose-dependent capillary leak syndrome with hypoalbuminemia, orthostatic hypotension, and weight gain. Patient 8 died on day 8 with severe capillary leak, bronchopneumonia, and rhabdomyolysis. All patients had progressive disease at 4 weeks except patient 8, who exhibited a near-complete remission before his death. This intensive schedule appears to produce inordinate toxicity with a maximal tolerated total dose of 8 mg/m2.

Safety and antitumor activity of apalutamide (ARN-509) in metastatic castration-resistant prostate cancer with and without prior abiraterone acetate and prednisone

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment. Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain. Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial

BACKGROUNDnThe optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety.nnnPATIENTS AND METHODSnA total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography.nnnRESULTSnThe 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy.nnnCONCLUSIONnThis 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity.nnnTRIAL REGISTRATIONnClinicalTrials.gov Identifier NCT00312208.

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide

BackgroundnMutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients.nnnPatients and methodsnBlood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6u2009months exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics GmbH).nnnResultsnOf the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12u2009months.nnnConclusionsnThe overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide.nnnClinicalTrials.gov identifiernNCT01171898.

A randomized, phase II study of the anti‐insulin‐like growth factor receptor type 1 (IGF‐1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

Overexpression of insulin‐like growth factor receptor type 1 (IGF‐1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron‐emission tomography in patients with chemotherapy‐refractory colorectal cancer treated with an anti‐insulin‐like growth factor receptor type 1 (anti‐IGF‐1R) monoclonal antibody, robatumumab. This was a randomized, open‐label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second‐line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUVmax). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUVmax (DiSUV) greater than 20% 12–14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)‐defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%–32%) had DiSUV greater than 20%. Fifty robatumumab‐treated patients were evaluable for RECIST‐defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy‐refractory colorectal cancer appeared to benefit from treatment with the IGF‐1R antagonist robatumumab.

Abstract B181: Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients

Background: The AKT pathway is critical in cancer initiation and progression, it can be constitutively activated by mutations in AKT (8% breast, 6% colorectal, 6.8% meningioma) and PIK3CA (27% breast, 28% endometrial, 13% colorectal)12. ARQ 092 is a potent and selective AKT inhibitor in phase 1 clinical development. Also, ARQ 092 has been shown to have anti-growth activity in cells from patients with Proteus syndrome, a non-cancer disease solely driven by AKT1E17K3. Methods: Biochemical IC50 for AKT 1/2/3 and the selectivity profile of ARQ 092 or ARQ 751 (more potent next generation AKT inhibitor) against over 300 kinases were determined. The binding of both inhibitors to wild-type AKT1 and AKT1E17K was assessed using intrinsic tryptophan fluorescence quench. Inhibitory effect on AKT1E17K was determined in transient transfection cell system. AKT1 membrane translocation was performed in cells transiently transfected with GFP-fused AKT1 or AKT1E17K. AKT pathway in select cell lines was assessed using Western blot analysis. Anti-proliferative effects were tested in a panel of 18 breast cancer cell lines, 4 with H1047R. In vivo efficacy was tested in 2 mouse xenografts and 2 patient-derived tumors with endometrial and breast cancer cells bearing AKT1E17K or PIK3CAH1047R mutations. In a phase 1 clinical trial, patients have been enrolled to receive oral ARQ 092 at multiple doses and schedules4. Results: ARQ 092 inhibited AKT1, 2, and 3 activity with IC50 values of 5.0, 4.5, and 16 nM, respectively whereas ARQ 751 had IC50 values of 0.54, 0.79, and 1.3 nM, respectively; MK-2206 exerted less potency (40.5, 29.5 and 36.4 nM) and GDC-0068 showed potency of 2.0, 27.0, and 6.3 nM. For the AKT1E17K mutant, Kd values were 42 and 8.6 nM for ARQ 092 and ARQ 751 respectively, accompanied with inhibition of its phosphorylation; whereas over 1 μM for MK-2206. ARQ 092 and ARQ 751 but not MK-2206 at 1 μM blocked AKT1E17K membrane translocation. ARQ 092 and ARQ 751 were efficacious on all 4 PIK3CAH1047R cells with GI50 of less than 1 μM. In an endometrial PDX model bearing AKT1E17K, ARQ 092 at 100 mg/kg and ARQ 751 at 75 mg/kg obtained respectively 78% and 98% tumor growth inhibition. In vivo models with PIK3CAH1047R treated with ARQ 092 at 100-120 mg/Kg exhibited tumor growth inhibition between 32% and 84%. In the ongoing clinical trial, in 7 patients with AKT1E17K enrolled at doses close to MTD for each schedule, 2 RECIST partial responses (breast cancer and follicular lymphoma), 2 minor responses (parotid cancer, 19.3% tumor reduction; endometrial cancer, 17.5% reduction), 3 stable diseases (ovarian, neuroendocrine, meningioma, 120-277 days on therapy) were observed. One patient with PIK3CAH1047R mutant endometrial carcinoma was treated and obtained a partial response. Conclusions: ARQ 092, and the next generation ARQ 751, are potent, selective allosteric AKT inhibitors. They both bind tightly to and inhibit membrane translocation and activation of AKT1E17K and of PI3K-stimulated AKT. Preclinical and clinical findings from oncology and non-oncology studies show that AKT1 E17K and PIK3CAH1047R mutations may be used for patient selection. 1Kim MS, Br J Cancer 2008. 2Yuan TL, Oncogene 2008. 3Biesecker L, ASHG 2014 4Tolcher A, ESMO 2015. Citation Format: Giovanni Abbadessa, Yi Yu, Sudharshan Eathiraj, Justin Meade, Michael J. Wick, Anthony Tolcher, Kyri Papadopoulos, Mansoor Saleh, Jasgit Sachdev, Feng Chai, Brian Schwartz. Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B181.

Academic Cancer Center Phase I Program Development

This commentary assesses the factors necessary for the effectiveness of academic phase I cancer programs. The metrics presented here may be useful as a rubric for new and established programs.