Timothy M. Lestingi

Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients

PURPOSE We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on disposition and toxicity of CPT-11. We tested the efficacy of acetaminophen (AAP) to phenotype SN-38 glucuronidation. PATIENTS AND METHODS Forty patients received a dose of 145 mg/m2 of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma and urine samples. Following administration of 1 g AAP, urinary concentrations of AAP and AAP-glucuronide (AAP-G) were assessed. RESULTS CPT-11 exhibited a mean elimination half-life (t1/2) of 8.8 hours, an average clearance (CL) of 14.6 L/h/m2, and a mean volume of distribution at steady-state (Vdss) of 136 L/m2. SN-38 and SN-38G had low plasma availabilities (3% and 10% relative to CPT-11), with mean t1/2 values of 11.6 and 10.5 hours, respectively. Urinary recovery accounted for 15% of the dose. Race and sex had no effect on the plasma availability of CPT-11, SN-38, and SN-38G. The applicability of biliary index (BI) in predicting dose-limiting intestinal toxicity was validated. Patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = .001). There was no difference in the incidence and severity of toxicity based on race and sex. AAP was a poor predictor of SN-38 glucuronidation. CONCLUSION The high degree of interpatient variability in parameter estimates suggests pharmacogenetic variation or differential induction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems. The low urinary recovery indicates substantial biliary excretion and supports the significant correlation between intestinal toxicity and BI. Black patients are not at increased risk of toxicity. An assessment of individual differences in SN-38 conjugation remains to be established.

Combination of Chemotherapy With Interleukin-2 and Interferon Alfa for the Treatment of Metastatic Melanoma

PURPOSE The primary objective of this clinical study was to assess the feasibility of administering recombinant interleukin-2 and recombinant interferon alfa-2a before and after combination cytotoxic chemotherapy. After encouraging initial responses, the study was expanded to further evaluate the therapeutic potential, clarify the toxicities of this regimen, and explore any associated immunologic changes. PATIENTS AND METHODS Eighty-four patients with metastatic melanoma, including patients with brain metastases, were treated on this 6-week protocol. Patients received combination cisplatin (25 mg/m2/d) and dacarbazine (220 mg/m2/d) on days 1 through 3 and 22 through 24 plus carmustine (150 mg/m2) on day 1. Interleukin 2 (13.5 million IU/m2/d) and interferon alfa (6 MU/m2/d) were administered on days 4 through 8 and 17 through 21. RESULTS Among 83 patients assessable for response, 12 complete and 34 partial responses were documented (55% response rate). The median time to disease progression was 7 months, the median survival from study entry was 12.2 months, and the median survival from diagnosis of metastatic disease was 15.5 months. Although patients were hospitalized to receive treatment, intensive care unit support generally was not needed. Dose-limiting toxicities were related to elevations in serum bilirubin and serum creatinine levels. No patient developed a grade 4 clinical toxicity. Treatment produced a skin depigmentation, which was associated with prolonged survival. CONCLUSION A plateau in both the survival and time to progression curves beyond 2 years (15% of the patients) and a greater than 10% disease-free survival beyond 4 years indicate that there may be a long-term benefit for some patients. The limited toxicity of this regimen should permit its use in most oncology settings. A randomized trial of chemoimmunotherapy versus chemotherapy should be performed to establish the value of chemoimmunotherapy for melanoma.

Lenalidomide Monotherapy in Chemotherapy-Naive, Castration-Resistant Prostate Cancer Patients: Final Results of a Phase II Study

BACKGROUND We investigated the activity of lenalidomide, which has antiangiogenic, antineoplastic, and immunomodulatory properties, in chemotherapy-naive, castration-resistant prostate cancer (CRPC) patients. PATIENTS Patients received 25 mg/d lenalidomide for 21 days in 28-day cycles, until disease progression or unacceptable toxicity developed. Endpoints included overall response rate and clinical benefit (overall response + stable disease), toxicity, time to radiographic progression, and time to prostate-specific antigen (PSA) progression, overall survival, and quality of life. RESULTS Thirty-two patients were enrolled in the study; of these, 77% (n = 25) had Gleason scores ≥ 7. The median age was 74 years (58-89 y), the median PSA level was 66 ng/mL (2-919 ng/mL), and 5 of 32 patients (17%) had liver or lung involvement. The median number of lenalidomide cycles was 3 (1-16 cycles). Stable disease was seen in 20 patients, for a clinical benefit rate of 63%. The median time to radiographic progression was 4 months (2-16 mo); the median overall survival was 20 months. Of 27 PSA-evaluable patients, 13 (48%) had a decline in PSA level; 3 (11%) had > 50% PSA decrease; the median time to PSA progression was 3 months (2-9 mo). Grade 3/4 hematologic toxicities were the most common adverse events without adverse impact on quality of life. Serious adverse events occurred in 14 patients (44%), including 1 patient (3%) with a rash definitely related to lenalidomide. CONCLUSION Lenalidomide monotherapy demonstrates modest activity in chemotherapy-naive CRPC.

Copper deficiency mimicking myelodysplastic syndrome.

Copper deficiency is a rare cause of pancytopenia that may be mistaken for myelodysplastic syndrome. Cytoplasmic vacuolization in erythroid and myeloid precursors is found on bone marrow examination. Patients with a history of abdominal surgery who present with anemia and neutropenia with dysplastic changes should have copper levels checked.

A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naive castration-resistant prostate cancer (CRPC): First report of suggested activity.

165 Background: PTEN tumor suppressor gene is mutated in CRPC allowing for downstream protein activation including mammalian target of rapamycin (m TOR) leading to tumor cell growth and survival. We investigated TEM; an mTOR inhibitor, in chemotherapy-naïve CRPC patients (pts). METHODS Eligible pts received TEM at 25 mg weekly until disease progression. Responses were assessed every 8 weeks and toxicity every 4 weeks using CTCAE v.3. Quality of life (QOL) data were collected every cycle using two previously validated scales. Primary end point: Clinical Benefit (CB) [sum of complete response (CR), partial response (PR), and stable disease (SD)]. Secondary end points: Toxicity, time to next treatment (TTNT), time to radiographic and PSA progression (TTP and TTP-PSA respectively), impact on QOL, and overall survival (OS) Results: To date, 18 pts have been enrolled. Median age was 75 (57-89) with Gleason ≥7 in 14 (77%), and median PSA 211.3 (10.8-1,449). Ten pts (55.5%) had bone and visceral disease. Median time on androgen deprivation therapy (ADT) was 60 months (17-240). Previous therapy included: surgery 3, brachytherapy 3, external radiation 5, ADT 7. All pts were evaluable for toxicity and 16 for response. Six pts (33%) were taken off study without progression (2 withdrew, 3 persitsant thrombocytopenia, 1 non-compliance). Biochemical response data was available for 15 pts (2 not evaluable, 1 refused), of which 4 (26%) had PSA decline and 1 (6%) had >50% drop in PSA. TTP-PSA was 2 months (2-12). Sixteen pts were evaluable by RECIST; 2 PR and 9 SD for a CB of 69% (11 of 16). TTP or event (toxicity that took pts off study was an event) was 3 months (3-10) and TTNT was 4 months (2-11). With a median follow up of 18 months, 8 pts (44%) remain alive for a median OS of 13 months. Most commonly reported grade 3/4 toxicities: Thrombocytopenia (22%), hyperglycemia, hypophosphatemia, and fatigue (17% each), pneumonia and anemia (12% each). TEM did not impact QOL adversely without treatment-related mortality. CONCLUSIONS TEM has activity in CRPC; some pts have CB without adverse impact on QOL. TEM should be further investigated in combination therapy in CRPC.

Etoposide combined with interferon alfa-2b : Novel exploitation of established etoposide pharmacokinetics and pharmacodynamics

To construct an efficient pilot study design to determine whether interferon alfa‐2b modifies the pharmacokinetics and pharmacodynamics of continuous‐infusion etoposide.

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 - 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LENs impact on quality of life (QOL). RESULTS 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). CONCLUSIONS LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

An Attempt to Quantitate “Value” In Medical Oncologic Therapy

Objective We wanted to examine the incremental cost-effective ratio (ICER) for a variety of Food and Drug Administration (FDA) approved oncology drugs in the adjuvant or curative setting to determine the value provided. Design We examined the annualized incremental drug costs of a variety of FDA approved chemotherapeutic drugs used in an adjuvant or curative setting based on National Comprehensive Cancer Network (NCCN) category 1 practice guidelines for melanoma, Her2/neu over-expressive breast cancer, renal cell carcinoma, stage IIIA non-small cell lung cancer, myeloma, B cell lymphoma, and Hodgkin lymphoma. The studies we examined were randomized clinical trials on which the NCCN guidelines are based; we solely examined the incremental cost-effectiveness of the trial drug as we assumed that the costs of the health care provided were equivalent between the two treatment arms. We used a formula to determine the incremental cost-effectiveness ratio (ICER). The ICER compares a new intervention (C new) with its alternate (C alt) divided by the quality-adjusted life-years (QALY) that results from the new intervention (QALY new) versus the alternate (QALY alt) and is expressed as ICER = (C new-C alt)/(QALY new-QALY alt). The QALY’s were derived from what was reported in the study and based on the incremental disease-free survival. Results Drugs such as rituximab provide high value in the curative therapy for lymphoma. Drugs such as adjuvant dabrafenib and trametinib provide intermediate value in the treatment of melanoma, and similarly with maintenance lenalidomide in myeloma and adjuvant trastuzumab in breast cancer. Oncologic drugs that provide low value include adjuvant ipilimumab in melanoma, adjuvant sunitinib in renal cell carcinoma, adjuvant neratinib in breast cancer, adjuvant durvalumab in lung cancer, and brentuximab in the curative therapy for Hodgkin’s lymphoma. Conclusion The ICER needs to be evaluated for newly approved FDA oncology chemotherapeutic drugs before incorporating them into routine clinical practice.

Phase I study of imatinib mesylate (IM) and sorafenib (S) in patients (pts) with refractory castration-resistant prostate cancer (CRPC).

146 Background: IM is an inhibitor of protein-tyrosine kinases including those that are over-expressed in bone metastases and primary prostatic adenocarcinoma. S is a potent inhibitor of wild-type and mutant BRAF, C-RAF, VEGFR2, VEGFR3, FLT3, and PDGFR-beta with modest activity in CRPC. We combined IM+S to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in CRPC pts. METHODS CRPC pts with measurable disease and adequate organ function who failed chemotherapy were eligible. Dose escalation followed a 3+3 study design. Toxicity was scored following CTCAEv3. Responses were defined by RECIST1.0. IM pharmacokinetics (PK) were determined on day 15, 4 h post-dose with a validated LC-MS assay. RESULTS Seventeen pts were enrolled; 10 were evaluable. At dose level 0 (DL0), 6 pts received S at 400 mg S with 300 mg of IM both given daily. At DL1, 4 pts received 400 mg S twice/day with 300 mg IM daily; inevaluable pts received <1 cycle (5 withdrew consent, 1 rapid early progression, 1 non-compliant). Median age was 73 (57-89) and median PSA was 284 ng/ml (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12) and 12 pts had Gleason score ≥7 while 15 pts had bone as the major site of metastases. On DL0, 1/6 pts had DLT (gr 3 hand/foot). On DL1, 2/4 pts had DLT (1 gr 3 hand/foot, 1 gr 3 diarrhea). MTD was 300 mg IM and 400 mg S both qd. No biochemical responses were observed. Two pts on DL1 had stable disease radiographically by RECIST (overall clinical benefit for the entire cohort 20%). Median time to progression was 2 months (1-5) while median OS was 6 months (1-30+) with 3/17 patients (17%) remaining alive at a median follow-up of 21 months. Of patients enrolled, 10 had PK data, which suggested that S reduced IM clearance by 40%, resulting in 60% increased exposure (P = 0.009; two-tailed t-test on log-transformed values, compared to historic data). CONCLUSIONS To our knowledge, this is the first report to show that IM+S can be safely combined in CRPC. The phase II recommended dose for future trials is 300 mg IM and 400 mg S, both given daily. The PK interaction might be of questionable clinical relevance because IM concentrations are within the commonly observed range.

Overcoming chemotherapy resistance in patients (pts) with chemotherapy-failure, castration-resistant prostate cancer (CRPC) with sorafenib.

127 Background: SOR is an oral multi kinase inhibitor that promotes apoptosis through downstream pathways that can be deregulated in CRPC leading to chemotherapy resistance. We hypothesized that SOR Could overcome chemotherapy resistance in non-responders or in those who progress shortly after stopping chemotherapy. METHODS Eligible pts were those who progressed while receiving chemotherapy [docetaxel (D) or mitoxantrone (M)] or within 12 weeks from stopping it. Pts were then continued or resumed on their last chemotherapy with the addition of SOR at 400 mg PO BID. Pts were allowed a maximum of 6 cycles of chemotherapy +SOR followed by SOR as monotherapy until progression. Primary end point: Safety of SOR+ chemotherapy. Secondary end points: Toxicity, time to progression (TTP). And responses (biochemical and radiographic) Results: Twenty-two pts were enrolled; 21 evaluable (73% Gleason ≥ 7). Median age was 68 (59-83). Median PSA was 142 ng/dl (13.6-9,584). Median time from last chemotherapy to SOR was 4 weeks. Visceral and bone disease was present in 64%. D was given in 16 pts while M in 6. Ten pts (45%) showed biochemical response (18% with >50% PSA decline). Despite progression before being on study, 16 pts (76%) achieved SD after starting SOR for a median duration of 6 months (4-12). The combination of SOR with either chemotherapy agent proved safe. Main grade 3/4 non-hematologic toxicities: Fatigue 7 (32%), 4 (18%) hand/foot syndrome, hypocalcemia and hyperglycemia in 2 pts (9%) each. Grade 3/4 leukopenia was seen in 7 (31%), neutropenia in 6 (27%), and thrombocytopenia in 2 (9%). Dose reduction of SOR occurred at least once in 15 pts (68%). Major reasons are hand/foot syndrome (22%), fatigue (22%), rash (13%), and neutropenia (9%). With a median follow-up of 19 months (3-46), 5 pts (23%) remain alive for a median OS of 8 months. TTP by PSA was 3 months (2-6) and TTP by imaging and/or clinically was 6 months (2-12). Median number of treatment cycles given was 6 (1-10). CONCLUSIONS SOR can safely be combined with chemotherapy. SOR overcomes chemotherapy-resistance and shows biochemical and radiographic stability in this refractory pt population.