Maximum Tolerated Dose Expansion Cohort Research Articles

A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients (pts) with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC).

3040 Background: AT-101 (AT) is an oral BH3 mimetic that lowers the apoptotic threshold by inhibiting heterodimerization of Bcl-2, Bcl-xL, Mcl-1 and Bcl-W, up-regulating pro-apoptotic proteins noxa and puma and inhibiting angiogenesis. Synergistic anti-tumor activity as been observed in vitro with EP in combination with agents that suppress Bcl-2 expression. This study was conducted to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic (PK) profile and preliminary anti-tumor activity of AT and EP. Methods: Adult pts with relapsed or refractory advanced solid tumors received AT orally BID days (D) 1-3, P IV D 1, and E IV D 1-3 of a 21-D cycle. We previously reported the MTD without pegfilgrastim (F) was AT 20 mg BID , P 60 mg/m2, and E 100 mg/m2 (Leal, JCO 2009; 27(15S), e13502). Pts were enrolled in 3 additional dose levels (DL) with F support (6 mg SQ day 4): DL1a (AT 30 mg, P 60 mg/m2, and E 100 mg/m2), DL2a (AT 30 mg, P 60 mg/m2, and E 120 mg/m2), and DL3a (AT 40 mg, P 60 mg/m2, and E 120 mg/m2). Results: 12 additional pts were enrolled: 8 men, 4 women. Tumor types: 4 non-small cell lung cancer (NSCLC), 1 ES-SCLC, 2 esophageal, 2 high-grade (HG) neuroendocrine, 1 prostate, 1 adrenocortical, 1 gallbladder. No dose limiting toxicities occurred. Grade 3/4 treatment-related toxicities included: 2 pts with diarrhea (1 at DL1a and 1 at DL3a), and 1 episode, each, of increased ALT (DL1a), hypokalemia (DL1a), fatigue (DL2a), neutropenia (DL2a), anemia (DL3a), hypophosphatemia (DL3a), and pulmonary embolism (DL3a). Dose-proportional PK was observed with a mean AT t1/2 of 3.32 hr (range 2.86-3.94). No PK interactions were observed between the agents. Two pts with NSCLC and 1 with HG neuroendocrine tumor had a PR. Conclusions: The MTD with F was established at AT 40 mg BID D1-3, P 60 mg/m2 D1, and E 120 mg/m2 D1 of a 21 D cycle. F support permitted standard doses of EP without dose limiting neutropenia. Anti-tumor activity was observed in NSCLC and HG neuroendocrine tumor. Accrual to an MTD expansion cohort of pts with untreated ES-SCLC is ongoing. This study was supported by NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011.

A phase I study of r-(-)-gossypol (AT-101, NSC 726190) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC).

e13030 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mcl-1, and Bcl-W. Combinations of AT and cytotoxic drugs demonstrated synergistic antitumor effects in vitro and in vivo SCLC models. We completed a dose-escalation study of AT in combination with cisplatin and etoposide (EP), in which neutropenia was dose- limiting. The objectives of this study were to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of AT when combined with EP with pegfilgrastim (F) in patients with advanced solid tumors. Methods: Standard phase I eligibility criteria were used. Prior therapy with Bcl2-inhibitors was not allowed. We previously reported the MTD without F established at AT 20 mg BID days (D) 1-3, P 60 mg/m2 D 1, E 100 mg/m2 D 1-3 every 21 days (Leal, JCO 2009; 27(15S), e13502). Patients were enrolled in 3 additional dose levels (DL) with F support (6 mg SQ D 4): DL1a (AT 30 mg BID, P 60 mg/m2, E 100 mg/m2), DL2a (AT 30 mg BID, P 60 mg/m2, E 120 mg/m2), and DL3a (AT 40 mg BID, P 60 mg/m2, E 120 mg/m2). Results: 12 patients were enrolled: 8 men, 4 women. Tumor types: 4 non-small cell lung cancer (NSCLC), 1 ES-SCLC, 2 esophageal, 2 neuroendocrine, 1 prostate, 1 adrenocortical, 1 gallbladder. No dose limiting toxicities occurred. Grade 3/4 treatment-related toxicities included: 2 episodes of diarrhea (1 DL1a, 1 DL3a), and 1, each, of elevated ALT (DL1a), hypokalemia (DL1a), fatigue (DL2a), neutropenia (DL2a), anemia (DL3a), hypophosphatemia (DL3a), and pulmonary embolism (DL3a). Two patients with NSCLC and 1 with neuroendocrine had a PR. Pharmacokinetic data will be available for presentation. Conclusions: The MTD/RP2D with F support was established at AT 40 mg BID on D 1-3, P 60 mg/m2 D 1, and E 120 mg/m2 D 1-3 every 21 days. F support permits full doses of cytotoxics to be administered. Antitumor activity was observed in patients with lung cancer and neuroendocrine tumor. Accrual to an MTD expansion cohort of patients with untreated ES- SCLC is ongoing. This study was supported by NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.

Safety, Pharmacokinetics, and Preliminary Clinical Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I Study

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors

4083 Background: Thymidylate synthase (TS) over-expression is associated with 5-FU resistance. Pre-clinical studies demonstrate that vorinostat down-regulates intra-tumor TS in a dose-dependent fashion and augments 5-FU antitumor activity in xenograft models. We conducted a phase I clinical trial of an intermittent schedule of QD x 3 vorinostat in combination with a fixed dose of fluorouracil (5-FU) and leucovorin (LV) in patients (pts) with refractory solid tumors. Methods: Vorinostat was escalated in a standard 3 x 3 design in combination with a fixed dose of 5-FU and LV (simplified de Gramont regimen, sFULV2). Vorinostat was given QD x 3 on an every-2-week cycle. sFULV2 started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hrs followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 over 46 hrs. Results: 24 pts were enrolled: Male/Female: 11/13; ECOG 0/1: 6/18; Age: median 60 (range 42–77) yrs. 21 pts had colorectal cancer (CRC), 1 had gastric, 1 had esophageal, and 1 had anal cancer. Vorinostat dose-levels (DL) were 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1700 mg, and 2000 mg. Dose-limiting toxicities (DLT), consisting of fatigue and hand-and-foot syndrome (H&F), were seen in 2 of 3 pts at the 2000 mg DL. None of the 6 pts at the 1700 mg DL had a DLT. Cycle 1 grade 3/4 toxicities consisted of thrombocytopenia, GI bleeding, fatigue, and H&F in 2 pts at the 2000 mg DL and a non-DLT G3 diarrhea (lasted <24 hrs) in 1 pt at the 1700 mg DL. Grade 2 nausea, fatigue, and anorexia were common; especially at DL ≥ 1700 mg. Antitumor activity was noted in pts with CRC despite prior refractoriness to 5-FU and failure to oxaliplatin, irinotecan, and cetuximab in all pts. 12/21 CRC pts had a confirmed SD (11) or PR (1). CRC pts had a median PFS of 4 months, a ≥ 6 months PFS rate of 43%, and a ≥ 8 months PFS rate of 33%. Conclusions: The maximum tolerated dose (MTD) of vorinostat in combination with sFULV2 is 1700 mg PO QD x 3 every 2 weeks. This combination is associated with considerable activity in pts with 5-FU-refractory CRC and warrants further investigation. An expanded MTD cohort is accruing to investigate 5-FU-vorinostat PK interaction and intra-tumor TS down-regulation. (This work was supported by a grant from CTEP and the ACS.) No significant financial relationships to disclose.

Safety and Clinical Activity of the Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) in Combination with Rituximab in Follicular Lymphoma or Diffuse Large B-Cell Lymphoma: Preliminary Report of a Phase 1/2 Study

Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Inotuzumab ozogamicin targets B-cell malignancies since they often express CD22. In a previously reported phase 1 dose-escalation trial in patients with CD22-positive B-cell non-Hodgkin's lymphoma (NHL), the maximum tolerated dose (MTD) was determined to be 1.8 mg/m2 every 4 weeks. Responses were seen in patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). This ongoing study consisted of a limited dose escalation (DE) portion to confirm the MTD of inotuzumab ozogamicin when combined with rituximab, followed by an expanded MTD cohort to further define safety and efficacy. Patients with FL and DLBCL who relapsed or progressed after 1 or 2 prior therapies were eligible. Prior rituximab treatment was required and prior autologous transplant allowed if >6 months from enrollment. Rituximab refractory patients, as defined by progression within 6 months of the first dose of rituximab, were excluded. Patients received rituximab 375 mg/m2 on day 1 of each 28-day cycle and inotuzumab ozogamicin on day 2 at doses of 0.8 mg/m2 (n=5), 1.3 mg/m2 (n=3), and 1.8 mg/m2 (n=7) for a maximum of 8 cycles. After confirmation of the MTD dose at 1.8 mg/m2 ditional patients were enrolled in an expanded MTD cohort. Safety data and preliminary efficacy data were collected. As of June 2008, the DE portion was completed and the study is enrolling in the MTD portion. To date, 61 patients have been treated: median age 63 yr (range 33–85 yr), 62% men. All 61 patients were evaluable for safety and currently 30 patients (16 FL, 14 DLBCL) in the expanded MTD cohort were evaluable for tumor response based on available data. 20% of patients discontinued treatment due to an adverse event (AE), which included hematologic AEs (8 patients) or elevation of ³1 liver function test (5 patients). The overall safety profile was characterized by AEs that were manageable; the most common drug-related AEs (all grades) were thrombocytopenia (41%), nausea (38%), fatigue (36%), AST increased (26%), and neutropenia (25%). Grade 3/4 AEs that occurred in 5% of patients included thrombocytopenia (21%), neutropenia (15%), and lymphopenia (7%). Tumor responses were seen in all DE cohorts and the MTD cohort, and the response rates in evaluable patients are shown in the Table. The 6-month progressionfree survival rate was 100% for FL and 66% DLBCL for all patients in the MTD cohort. The safety profile of inotuzumab ozogamicin plus rituximab exhibits a similar profile seen in the previous inotuzumab ozogamicin monotherapy study. The main toxicity was clinically manageable, self-limited thrombocytopenia. The preliminary efficacy in recurrent/refractory FL and DLBCL is promising and may indicate a durable response. These data support the continuing development of inotuzumab ozogamicin in combination with rituximab in the management of NHL.Table: Best Overall Response, Evaluable* Patients in the Dose Escalation (DE) and MTD CohortsFL, n (%)DLBCL, n (%)DEMTDDEMTDResponse0.8 (n=1)1.3 (n=2)1.8 (n=3)Total (n=6)1.8 (n=16)0.8 (n=3)1.3 (n=1)1.8 (n=2)Total (n=6)1.8 (n=14)CR/CRu1 (100)1 (50)1 (33)3 (50)7 (44)1 (33)01 (50)2 (33)6 (43)ORR1 (100)2 (100)2 (67)5 (83)14 (88)1 (33)1 (100)2 (100)4 (67)10 (71)CR=complete response; CRu=CR unconfirmed;ORR=objective response rate (CR/CRu+partial response)*Best response during treatment and follow up.Evaluable patients had 32 doses inotuzumab ozogamicin and a response assessment

A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood

A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.

Phase I trial of the mTOR inhibitor RAD001 (R) in combination with two schedules of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor PTK787/ZK 222584 (P) in patients (pts) with advanced solid tumors

2529 Background: There is synergistic antitumor effect between mTOR inhibitors and anti-angiogenesis agents. Methods: A phase I study was performed to define the maximum tolerated dose (MTD) and clinical activity of both QD dose and BID dose of P in combination with R (see table) q28 days in pts with advanced cancers. Correlative markers of response and therapy-induced hypertension were analyzed. Results: 24 pts at dose escalation phase and 24 pts at expanded MTD cohort received 233 cycles of therapy. Major toxicities (cumulative events, CTC grade) were ALT elevation (3 gr 3), diarrhea (6 gr 3), vomiting (5 gr 3), fatigue (5 gr 3), hypercholesterolemia (1 gr 3 and 1 gr 4 ), hypertriglyceridemia (6 gr 3), hypertension (6 gr 2 and 1 gr 3), proteinuria (10 gr 2), thrombosis (1 gr 3 and 1 gr 4). DLTs were gr 3 ALT elevation and diarrhea. Dose level 3 was used for the expanded MTD cohort due to better pharmacokinetic and toxicity profile with chronic dosing. PRs were seen in 6 pts: 2 neuroendocrine carcinoma (NEC), 2 treatment-naïve clear cell renal cell cancer (RCC), 1 uterine serous carcinoma, 1 melanoma. 9 pts had SD lasting >5 cycles. There was temporal decrease in plasma sVEGFR1 and increase in VEGF-A levels. There was no significant change in flow-mediated dilated (FMD) measured by brachial artery US. There was no correlation between BP change with VEGF-A, sVEGFR1 or FMD. DCE-MRI in 4 pts showed temporal reduction in maximal slope of increase and signal enhancement ratio (SER). Adjusting for normal control tissue, there was temporal increase in SER except in the pt with disease progression. Conclusions: The combination of P with R is effective and well tolerated. There is no correlation between BP change with VEGF-A, sVEGFR1 or FMD. Absolute temporal changes of vascular parameters in DCE-MRI do not predict for treatment response. We recommend the BID schedule of P with R for future evaluation in phase II studies for RCC and NEC. Dose Level R (mg, QD) P ( mg) No. pts (No. replaced) No. cycles No. DLTs 0* 5 1,000 QD 3 (3) 38 0 1 10 1,000 QD 3 14 0 2 10 1,250 QD 6 21 1 3 10 750 BID 6 (1) 45 1 4 10 1,000 BID 6 (2) 19 0 No significant financial relationships to disclose.

Preliminary Report of a Phase 1 Study of CMC-544, an Antibody-Targeted Chemotherapy Agent, in Patients with B-Cell Non-Hodgkin's Lymphoma (NHL).

Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a monoclonal antibody, which specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor antibiotic. Malignant cells of mature B-lymphocyte lineage express CD22 and thus, CMC-544 may be useful for treating lymphomas of B-cell origin.Methods: A phase 1, dose escalation trial of CMC-544 is ongoing in patients (pts) with relapsed or refractory B-cell NHL across 13 European and US sites. CMC-544 was administered intravenously every 3–4 weeks at doses of 0.4, 0.8, 1.34, 1.8, and 2.4 mg/m2. Standard safety and pharmacokinetic data and preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) are being collected. Enrollment of pts with any type of B-cell NHL, except for Burkitt's and lymphoblastic lymphomas, was allowed in the dose escalation phase (1–6 pts per cohort). After the maximum tolerated dose (MTD) was identified, 15 pts with follicular lymphoma and 15 pts with diffuse large B-cell lymphoma will be enrolled in an expanded MTD cohort.Results: As of June 2005, 34 pts (8 women, median 71 yrs; 26 men, median 62 yrs; number of previous treatments, median 4, range 2–11) were enrolled. Dose escalation was based on 1st cycle safety evaluations of pt cohorts. Dose-limiting toxicities (DLTs) were reported for dose levels of 1.34 mg/m2 (grade 4 thrombocytopenia, 2/11 pts), 1.8 mg/m2 (bleeding requiring platelet transfusion, 1/6), and 2.4 mg/m2 (grade 4 thrombocytopenia, 1/6; grade 4 neutropenia for 7 days, 1/6). Thus, the MTD, the dose level prior to the one where ≥ 33% DLTs occurred, was 1.8 mg/m2. The most common drug-related adverse events (AEs, all grades) were: thrombocytopenia (65%), asthenia (47%), nausea (41%), neutropenia (29%), elevated liver function tests (27%), anorexia (14%), and epistaxis (12%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included: thrombocytopenia (38%), asthenia (12%), and neutropenia (12%). The nadir of the thrombocytopenia was 9±2 days and platelet counts recovered spontaneously. No major bleeding episodes were reported. At the 1.8 and 2.4 mg/m2 dose levels, data suggested a dose-dependent component of platelet recovery to baseline levels and dose delays were required between successive doses. CMC-544 and total calicheamicin exposures in serum increased with dose. Clearance after 2nd or 3rd doses decreased approximately 8–14-fold compared with 1st dose, and half-life increased from approximately 1 day to 4 days. Available data suggested an association of peak CMC-544 exposures and/or total calicheamicin levels with decreases in platelet counts. Accordingly, pts in the expanded MTD cohort receive 1.8 mg/m2 CMC-544 every 4 weeks. Preliminary antitumor activity was observed in most cohorts. Complete and/or partial responses were observed in the 0.8 mg/m2 (1/3 pts), 1.34 mg/m2 (3/9), 1.8 mg/m2 (2/5), and 2.4 mg/m2 (2/5) cohorts, and in the 1st 6 pts in the expanded MTD cohort (4/6).Conclusion: CMC-544 shows promising preliminary efficacy in pts with B-cell NHL, with an associated thrombocytopenia that is clinically manageable. The expanded MTD cohort (1.8 mg/m2 every 4 weeks) continues to be enrolled.