A Phase 1 Study of LY2874455 in Participants With Advanced Cancer

Study Overview
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Brief Summary
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The study is to determine the recommended Phase 2 regimen of study drug that may be safely administered to participants with advanced and or metastatic cancer. The study consists of two parts: a dose escalation and a dose confirmation.

Detailed Description
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Phase 1, first human dose study

Official Title
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A Phase 1 Study of LY2874455 to Assess Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy in Patients With Advanced Cancer.

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: FGF Receptor
* Drug: Phosphate Binders


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histological or cytological evidence of a diagnosis of cancer (solid tumors, lymphoma, or chronic lymphocytic leukemia) that is advanced and/or metastatic and for which all standard therapies have failed Have the presence of measurable or non-measurable disease Have given written informed consent prior to any study-specific procedures Have adequate organ function including: Hematologic: Absolute neutrophil count (ANC) equal to or greater than 1.5 x 10(9)/L platelets equal to or greater than 100 x 10(9)/L, and hemoglobin equal to or greater than 8 g/dL. Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin until 14 days after the erythrocyte transfusion Hepatic: Bilirubin equal to or less than 1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) equal to or less than 2.5 times ULN. If the liver has tumor involvement, AST and ALT equaling equal to or less than 5 times ULN are acceptable Renal: Serum creatinine less than or equal to 1.2 times ULN or calculated creatinine clearance greater than or equal to 60 milliliters per minute using the Standard Cockcroft and Gault Creatinine Clearance Calculation Calcium and phosphate less than or equal to 1.1 times ULN Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale Have discontinued chemotherapy and cancer-related hormonal therapy with commercially available agents for at least 21 days (6 weeks for mitomycin-C or nitrosoureas) and radiotherapy for at least 14 days prior to study enrollment and recovered from the acute effects of therapy. Hormone refractory prostate cancer participants receiving gonadotropin releasing hormone (GnRH) agonist therapy or breast cancer participants on antiestrogen therapy (for example, an aromatase inhibitor) prior to entrance on the study may have that treatment continued while they are enrolled in the study Females with childbearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug. Males and females with reproductive potential must agree to use 2 medically approved contraceptive methods during the trial and for 3 months following the last dose of study drug. Female participants must agree to use 2 medically acceptable methods of contraception, 1 being an oral contraceptive, dermal patch, or progestin (implantation or injection), and the other being a medically acceptable barrier method; alternatively, 2 medically acceptable barrier methods may be used. Medically acceptable barrier methods of contraception that may be used by the participant and/or his/her partner include: abstinence; diaphragm with spermicide; intrauterine device (IUD); condom together with foam, spermicide, or vaginal spermicidal suppository. Prohibited methods include the rhythm method, withdrawal, condoms alone, or diaphragm alone Have an estimated life expectancy of greater than or equal to 12 weeks Exclusion Criteria: Have received treatment with an investigational drug, which has not received regulatory approval for any indication, within 28 days of study treatment with LY2874455 Currently taking agents to control serum phosphate or calcium levels. This includes dietary restrictions Have medical conditions that, in the opinion of the investigator, would preclude participation in this study Have symptomatic central nervous system (CNS) malignancy or metastasis. Participants with treated CNS metastases are eligible provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Screening of asymptomatic participants without history of CNS metastases is not required Have a history of major organ transplant (for example: heart, lungs, liver, and kidney) Have current acute leukemia Females who are pregnant or nursing An untreated or uncontrolled acute infection, including urinary tract infection, within 7 days of study entry Have Bazett's corrected QT (QTcB) greater than 470 msec (female) or greater than 450 msec (male), history of unexplained recurrent syncope, history of congenital long QT syndrome, family history of sudden death, or the presence in the screening electrocardiogram (ECG) of a conduction abnormality that in the opinion of the investigator would preclude safe participation in this study Have had an autologous or allogenic bone marrow transplant Previously treated with LY2874455

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: 2 mg FGF Receptor QD<br>Part A: Dose escalation 2 milligrams (mg) FGF receptor given orally once daily (QD) for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 4 mg FGF Receptor QD<br>Part A: Dose escalation 4 mg FGF receptor given orally QD for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 10 mg FGF Receptor QD<br>Part A: Dose escalation 10 mg FGF receptor given orally QD for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days). | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 10 mg FGF Receptor QD + Phosphate Binders<br>Part A: Dose escalation 10 mg FGF receptor + phosphate binders given QD for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;Drug: Phosphate Binders<br> <br> |
| Experimental: Part A: 8 mg FGF Receptor BID<br>Part A: Dose escalation 8 mg of FGF receptor given orally twice a day (BID) for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 10 mg FGF Receptor BID<br>Part A: Dose escalation 10 mg FGF receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 14 mg FGF Receptor BID<br>Part A: Dose escalation 14 FGF receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 18 mg FGF Receptor BID<br>Part A: Dose escalation 18 mg FGF receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 24 mg FGF Receptor BID<br>Part A: Dose escalation 24 mg FGF receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days). | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 18 mg FGF Receptor BID Extension<br>Part A: Dose escalation 18 mg FGF Receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part A: 16 mg FGF Receptor BID<br>Part A: Dose escalation 16 mg FGF Receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|
| Experimental: Part B: 16 mg FGF Receptor BID<br>Part B: Dose determined by part a dose escalation 16 mg FGF Receptor given orally BID for a minimum of (1) 28 day cycle. If participants are determined to be receiving benefit, study treatment may be continued for up to one (1) year (12 cycles of 28 days) | Drug: FGF Receptor<br>* LY2874455 administered orally.<br>* Other names: LY2874455;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose for Phase 2 Studies : Maximum Tolerated Dose (MTD) | MTD was determined after the evaluation of Part A portion of the trial. Dose escalation proceeded at 1.3 times the preceding cohort once a Grade 3 non-laboratory toxicity or Grade 2 laboratory toxicity was noted in ≥ 1 participant until MTD was achieved. Doses up to 24 mg (48 mg/day) were evaluated in Part A. The effects at this dose and at 18 mg (36 mg/day) suggested that a reasonable number of participants might not tolerate LY2874455 for chronic administration at these dose levels because of the constellation of effects observed individually or in combination in participants at these dose levels. Therefore, the dose of 16 mg BID of LY2874455 (total dose 32 mg per day) was selected as the initial dose for Part B. Selection of the dose level was based on the tolerability of this dose and without specific toxicities identified. | Baseline Up to 32 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events | Treatment-emergent adverse events (TEAEs) are events which were not present at baseline or pre-existing conditions at baseline that worsened in severity following the start of treatment. A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section. | Baseline Up to 60 Weeks | 
| Percentage of Participants With Best Overall Response Rate (BORR) and Objective Response Rate (ORR) | BORR is evaluated using response evaluation criteria in solid tumors (RECIST, version 1.1) criteria. Complete Response (CR): disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 millimeters (mm). Partial Response (PR): at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Best overall response rate = (unconfirmed CR+ unconfirmed PR) / subjects in efficacy population. Objective response rate = (confirmed CR+ confirmed PR) / subjects in efficacy population. | BORR: Baseline Up to 60 Weeks ; ORR: Baseline Up to 60 Weeks | 
| Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY2874455 | Maximum observed concentration during a dosing interval. | Part A and B: Cycle 1, Day 1, Pre-Dose, 0.5 Hr (H), 1 H, 2 H, 4H,8 H,12 H,24 H; Day 28, Pre-Dose, 0.5 H, 1 H, 2 H, 4 H, 8 H | 
| Pharmacokinetics (PK): Area Under the Concentration vs Time Curve 0 to Tau ( AUC[0-t]) of LY2874455 | Area under the concentration-time curve from time 0 to the end of the dosing interval (e.g., BID) calculated by a combination of linear and logarithmic trapezoidal methods (linear-up/log-down method). | Part A and B: Cycle 1, Day 1, Pre-Dose, 0.5 Hr (H), 1 H, 2 H, 4H,8 H,12 H,24 H; Day 28, Pre-Dose, 0.5 H, 1 H, 2 H, 4 H, 8 H | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced cancer, Metastatic cancer, Oncology