A Phase I Study of Weekly Topotecan in Combination with Pemetrexed in Patients with Advanced Malignancies

Introduction.

This phase I study evaluated the safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan (days 1 and 8) in combination with pemetrexed (day 1 only) in patients with advanced solid tumors.

Methods.

Patients received topotecan (3.0–4.0 mg/m² i.v. days 1 and 8) and pemetrexed (375–500 mg/m² i.v. day 1) over 21-day cycles. Patients were accrued across five different dose levels and were observed for safety, tolerability, and preliminary activity.

Results.

Twenty-six patients received 120 cycles of pemetrexed and topotecan, including five patients who received 8, 8, 10, 12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients received topotecan (4.0 mg/m² i.v.) and pemetrexed (500 mg/m² i.v.), but experienced two dose-limiting toxicities (febrile neutropenia, grade 4 thrombocytopenia). As a result, the topotecan (3.5 mg/m² i.v.) and pemetrexed (500 mg/m² i.v.) group was expanded to 12 patients. The only grade 3 or 4 nonhematologic toxicity was one episode of grade 3 fatigue; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. One non-small cell lung cancer (NSCLC) patient (12 months) and one soft tissue sarcoma patient (6 months) achieved a partial response.

Conclusions.

Weekly topotecan plus every-3-week pemetrexed was well tolerated and active. Full doses of topotecan plus pemetrexed caused brief reversible myelosuppression with minimal dose delays/reductions; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. All six NSCLC patients at the recommended phase II dose had at least stable disease as a best response, including one partial response lasting 12 months. There was no evidence of an effect of pemetrexed on topotecan pharmacokinetics. Collectively, these data suggest that further phase II exploration of weekly topotecan plus every-3-week pemetrexed for advanced malignancies is indicated.     

Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation

BackgroundPatients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation.MethodsEligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method.ResultsTen patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non–small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3–4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%).ConclusionBased on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT04006301","term_id":"NCT04006301"}}NCT04006301     

A Phase I,First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody,in HER3-Expressing Solid Tumors

Background

GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors.

Patients and Methods

Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4–30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly.

Results

Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC).

Conclusion

GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion–positive cancers.

Implications for Practice

This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity– and complement-dependent cytotoxicity–enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.

     

Efficacy and Safety of Endostar Combined with Chemotherapy in Patients with Advanced Solid Tumors

Purpose: Endostar® is a proteolytic fragment of collagen XVIII that has been shown to have antitumor activity, with a favorable toxicological profile. We conducted this study to investigate its efficacy and safety when combined with chemotherapy in patients with advanced solid tumors. Methods: From July 2006 to September 2008, 45 patients with histologically or cytologically confirmed solid tumors were enrolled into this study. All received Endostar at a dose of 7.5 mg/m2/day as an intravenous infusion for more than 7 days, in combination with chemotherapy. Patients were treated until tumor progression or unacceptable toxicity. Results: No treatment related death occurred in this study. Main reported toxicities included: mylosuppression (82.2%), hepatic impairment (42.2%), anorexia (20.0%), nausea (24.4%), vomiting (22.2%), diarrhea (20.0%), febrile (20.0%) and fatigue (24.4%). No complete response was observed. Two patients (2/42) had partial response, twenty-one (21/42) remained stable, and nineteen (19/42) had progressive disease. Median time to tumor progression was 3.0 months (range, 0.5-12.0). Median overall survival was 30.0 months (95% confidence interval: 20.0-40.0) and 1 year survival rate was 81.0%. Conclusion: Our study revealed that toxicity of Endostar combined with chemotherapy in the treatment of solid tumors was tolerable with moderate efficacy.     

Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody,in Patients with Advanced Solid Tumors

Background

CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types.

Objective

The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study.

Materials and Methods

In phase 1a, patients (n?=?31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03–1.0 mg/kg) intravenously once weekly using a standard 3?+?3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n?=?15) and pancreatic (n?=?16) cancer, respectively, received the maximum tolerated dose (MTD).

Results

The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N?=?62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %).

Conclusions

The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732].

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A Novel Combretastatin A-4 Derivative, AC-7700, Shows Marked Antitumor Activity against Advanced Solid Tumors and Orthotopically Transplanted Tumors

AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2–0.5 cm³, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm³. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-α production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.     

Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors

PURPOSE: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. EXPERIMENTAL DESIGN: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. RESULTS: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C(max) occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma. CONCLUSION: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types. Clin Cancer Res; 18(17); 4806-19. ?2012 AACR.     

Phase Ib Study of High-dose Intermittent Afatinib in Patients With Advanced Solid Tumors

Background

The present phase Ib study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of high-dose intermittent (HDI) afatinib monotherapy for patients with advanced solid tumors. The planned focus was patients with epidermal growth factor receptor (EGFR) T790M⁺ non–small-cell lung cancer (NSCLC).