Mark U. Rarick

Use of Epoetin in Patients With Cancer: Evidence-Based Clinical Practice Guidelines of the American Society of Clinical Oncology and the American Society of Hematology

Anemia resulting from cancer or its treatment is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin (Hgb) concentration below 10 g/dL. Use of epoetin for patients with less severe anemia (Hgb level below 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40 000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6-8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.

Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

PURPOSE TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome

Ezatiostat is a glutathione analog prodrug glutathione S‐transferase P1‐1 (GSTP1‐1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate‐1 risk myelodysplastic syndrome (MDS).

Abstract LB-121: Randomized phase II study of the efficacy and safety of gemcitabine + TH-302 (G+T) vs gemcitabine (G) alone in previously untreated patients with advanced pancreatic cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL A hypoxic microenvironment is believed to be a characteristic of solid tumors including pancreatic adenocarcinoma (PAC) and is associated with resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to specifically target the hypoxic microenvironment. Combining G with TH-302 may enable the targeting of both the normoxic and hypoxic regions of PAC. TH-302 was investigated with full-dose G as part of a Phase 1/2 study with a 21% response, median PFS and OS of 5.9 and 8.5 months, respectively, and one-year survival of >40%. Based upon these data, a randomized Phase 2B study ([NCT01144455][1]) was conducted to assess the benefit of G+T to standard dose G for first-line therapy of PAC. An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1) was initiated in June 2010. G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G arm could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint is a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). 214 pts (69 G: 71 G+T240: 74 G+T340) with advanced PAC including 77% distant metastases, 62% involving liver and 11% with prior adjuvant tx; median age: 65 (range 29-86); 126 M/88 F; 79/128 ECOG 0/1. Median cycles received: G - 4, G+T240 - 5, G+T340 - 6. Median PFS was 3.6 mo in G vs 5.6 mo in G+T arms with HR of 0.61 (95% CI: 0.43 - 0.87) and logrank p-value of 0.005. Median PFS in G + T340 was 6.0 mo. RECIST best response was 12% in G, 17% in G+T 240 and 27% in G+T340. 153 (71%) patients had elevated CA19-9 and follow-up. CA19-9 decreases were significantly greater in the G+T groups and greatest in the G+T340 arm which had 37 of 53 (70%) pts with a greater than 50% CA19-9 decrease. One death (suicide) was considered possibly related to study drug. Adverse events leading to discontinuation were: 16% G, 15% G+T240 and 11% G+T340. Serious adverse events were balanced across the treatment arms. The most common non-laboratory events, fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (38%), were similar across groups. Rash (14% G, 39% G+T240 and 45% G+T340) and stomatitis (6% G, 17% G+T240 and 36% G+T340) were significantly greater with G+T combination but no Grd 4 (4 pts with Grade 3). Grd 3/4 thrombocytopenia (11% G, 39% G+T240 and 59% G+T340) and Grd 3/4 neutropenia (28% G, 56% G+T240 and 59% G+T340) were higher with G+T. G+T combination with full dose G improved the efficacy of G with significantly longer PFS, higher response rate and greater CA19-9 declines. The G+T combination was well tolerated. Skin and mucosal toxicity and myelosuppression were the most common related adverse events with no increase in treatment discontinuation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-121. doi:1538-7445.AM2012-LB-121 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01144455&atom=%2Fcanres%2F72%2F8_Supplement%2FLB-121.atom

Abstract 4660: A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer.

Tumor regrowth after chemotherapy may be driven by growth of tumor ‘stem cells’. Telomerase, required for indefinite replication, is upregulated in tumor progenitor cells. Imetelstat is a 13-mer oligonucleotide which is a potent and specific telomerase inhibitor. Progression-free survival (PFS) and the duration of responses after 1st-line chemotherapy for non-small-cell lung cancer (NSCLC) are short, which has led to an interest in developing active maintenance therapies. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in NSCLC. Pts were eligible with advanced NSCLC not progressing after completing 4-6 cycles of platinum-based doublet induction chemotherapy, any NSCLC histology, performance status (PS) ECOG 0 or 1, and not scheduled to receive maintenance with pemetrexed or erlotinib. Pts were randomized 2:1 to imetelstat 9.4 mg/kg (d1 and 8 of a 21d cycle) or observation until progressive disease or unacceptable toxicity (concomitant use of bevacizumab was permitted). The 1 o endpoint was PFS; safety/tolerability and objective response rate were 2 o endpoints. 116 pts were enrolled between Jul 2010 to Apr 2012, with 114 completing a first visit (i.e. efficacy population). Baseline characteristics of age, gender, PS and number of induction cycles were well balanced. 18.4% had squamous histology; 31.6% received concomitant bevacizumab (bev). The median number of imetelstat maintenance cycles was 3. In the overall analysis of PFS, a non significant improvement in favor of the imetelstat arm was observed (HR = 0.77, P=0.295, 95% CI 0.48 - 1.25). Median PFS was 2.8m for imetelstat and 2.6m for control. In the subgroup of patients who did not receive bevacizumab, the HR was 0.59 (vs. 1.07 for the bevacizumab subgroup; interaction P=0.15). The objective response rate was 4.3% in the imetelstat arm and 2.8% in the control arm. Six month overall survival was 80% for imetelstat and 72% for control (HR = 0.86, P=0.642, 95% CI 0.44 - 1.66). Imetelstat was generally well tolerated although hematologic toxicity, predominantly neutropenia and thrombocytopenia, was increased in the imetelstat arm (grade 3/4 neutropenia 18% for imetelstat vs 0% for control, grade 3/4 thrombocytopenia 37% for imetelstat vs 0% for control). The most frequent non-hematologic toxicities were fatigue (imetelstat 42.1% vs control 18.4%), nausea (43.4% vs 7.9%), vomiting (25.0% vs 5.3%) and anaemia (19.7% vs 5.3%). The overall findings suggest that imetelstat has modest, but not clinically meaningful, activity as a maintenance therapy in pts with NSCLC. A pre-specified exploratory subgroup analysis of PFS by tumor telomere length is reported separately. Citation Format: Alberto Chiappori, Tatjana Kolevska, Bart Burington, David Spigel, Steven Hager, Mark Rarick, Shirish Gadgeel, Normand Blais, Joachim Von Pawel, Lowell Hart, Martin Reck, Joan Schiller. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2013-4660

Abstract 2376: Improved progression-free survival (PFS) in patients with short tumor telomere length: Subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC .

Tumor regrowth after chemotherapy may be driven by growth of tumor ‘stem cells’. Telomerase, required for indefinite replication, is upregulated both in putative ‘stem cells’ and bulk tumor cells. Imetelstat, a lipidated 13-mer oligonucleotide, is a potent and specific inhibitor of telomerase. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in advanced NSCLC: results for the primary and secondary endpoints are reported separately. NSCLC cell lines and other tumor cells with short telomeres appear to be more sensitive to imetelstat in vitro than those with long telomeres. A planned exploratory analysis to determine PFS as a function of tumor telomere length (TL) was performed. Tumor TL was assessed in archival tumor specimens from pts by quantitative PCR (qPCR). TL data were available for 57 of the 116 pts accrued in the clinical trial. PFS was evaluated in patients grouped into the shortest 1/2, shortest 1/3 and shortest 1/4 of TL. In 19 pts with the shortest 1/3 TL measured by qPCR, imetelstat maintenance increased PFS with a HR in favor of the imetelstat arm of 0.32 (95% CI 0.1 to 1.0), p=0.042 (un-stratified log rank). Median PFS was 4.0 months for the imetelstat-treated short TL sub-group and 1.5 months for the control short TL sub-group. In the 38 pts with the longest 2/3 TL HR was 0.83 (95% CI 0.36 to 1.9). Results in the group with the shortest 1/4 of TL were similar to the shortest 1/3 TL group, and in the shortest 1/2 group, results were consistent but attenuated, indicating that a smaller subset may contain patients with the most potential to benefit. In the control arm, short TL was associated with shorter median PFS (1.48 months) compared to patients with long TL (2.7 months), suggesting that short TL has a negative prognostic value. These findings suggest that imetelstat given as maintenance therapy prolongs PFS in pts with advanced NSCLC whose tumors have short telomeres as measured by qPCR. The data are consistent with the hypothesis that clinical benefit from telomerase inhibition is greater in patients with tumors possessing short telomeres. Prospective confirmation of these results in solid tumors and hematologic neoplasms is planned. Citation Format: Alberto Chiappori, Ekaterina Bassett, Bart Burington, Tatjana Kolevska, David R. Spigel, Steven Hager, Mark Rarick, Shirish Gadgeel, Normand Blais, Joachim Von Pawel, Lowell Hart, Hui Wang, Kevin Eng, Martin Reck, Joan Schiller. Improved progression-free survival (PFS) in patients with short tumor telomere length: Subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2376. doi:10.1158/1538-7445.AM2013-2376