| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase I: Patients with solid malignancy unlikely to benefit from approved therapies.
Phase II: Patients with pancreatic cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
Phase I: Patients with cancer who can not be cured by surgery or drug.
Phase II: Patients with pancreatic cancer who can not be cured by surgery or drug.
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033612 |
| E.1.2 | Term | Pancreatic carcinoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1: Primary objective is to determine the recommended Phase 2 dose of LY2603618 when administered 24 hours after treatment with gemcitabine 1000 mg/m2 IV in patients with solid malignancy.
Phase 2; Primary objective is to determine if overall survival in patients with Stage II-IV unresectable pancreatic cancer administered LY2603618 plus gemcitabine exceeds gemcitabine monotherapy |
|
| E.2.2 | Secondary objectives of the trial |
Phase I: To characterize the preliminary safety and toxicity profile of LY2603618
when administered after gemcitabine, evaluate the preliminary PKs of gemcitabine,dFdU and LY2603618 in combination, antitumor activity observed after administration of LY2603618 and gemcitabine, explore biomarker responses associated with LY2603618 and gemcitabine combination, assessment of the potential effect of LY2603618 on QTc prolongation.
Phase II:
To characterize further the safety and toxicity profile of LY2603618 when
administered after gemcitabine and to compare it to the safety profile of
gemcitabine monotherapy, stimate other time-to-event variables, explore the percentage change in tumor size at 8 weeks, document response rate per RECIST, evaluate the PKs of gemcitabine, dFdU and LY2603618 in combination, assess biomarker responses associated with LY2603618 and gemcitabine combination, perform an exploratory assessment of QTc. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Phase 1 portion: Have histological or cytological evidence of a
diagnosis of cancer that is advanced and/or metastatic disease; that is
refractory to standard therapy and/or therapies known to provide
clinical benefit or for which no standard therapy exists; and/or in
which gemcitabine therapy at the proposed doses and schedule would
be considered appropriate treatment for the metastatic disease.
[2] Phase 2 portion: Histological or cytological diagnosis of
adenocarcinoma of the pancreas that is locally advanced (Stage II, III)
or metastatic (Stage IV) and not amenable to resection with curative
intent.
[3] For Phase 2 only: Have measurable disease or non-measurable
disease, defined according to RECIST
[4] Males or females at least 18 years of age
[5] Have given written informed consent prior to any study-specific
procedures.
[6] Have adequate organ function(hematologic, hepatic, renal)
[7] Have a performance status of ≤2 on the ECOG scale
[8] For Phase 1: Patients enrolling in Phase 1 portion of study may have
prior chemotherapy, radiotherapy, cancer-related hormone therapy, or
other investigational therapy as treatment. There is no limit in the
number of previous lines of therapy.
For Phase 2: Patients may have received previous adjuvant treatment
with gemcitabine with or without radiotherapy for pancreas cancer.
[9] Are reliable and willing to make themselves available for the duration
of the study and are willing to follow study procedures.
[10] Males and females with reproductive potential must agree to use
medically approved contraceptive precautions during the trial until the
patient’s physicians deems it safe to become pregnant or father a child.
[11] Females with child bearing potential must have had a negative urine
pregnancy test ≤7 days prior to the first dose of study drug.
[13] Prior radiation therapy for treatment of cancer other than pancreatic is
allowed to <25% of the bone marrow, and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed.
[14] Baseline ECG QTc interval corrected by Bazett’s method (should be <450 msec for males and <470 msec for females. |
|
| E.4 | Principal exclusion criteria |
[15] Are currently enrolled in, or discontinued within the last 30 days from,
a clinical trial involving an off-label use of an investigational drug or
device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[16] Have serious preexisting medical conditions or serious concomitant
systemic disorders that would compromise the safety of the patient or
his/her ability to complete the study, at the discretion of the
investigator
[17] Have symptomatic central nervous system malignancy or metastasis
[18] Have current active infection that would, in the opinion of the
investigator, compromise the patient’s ability to tolerate therapy.
[19] Females who are pregnant or lactating.
[20] Have known positive test results in human immunodeficiency virus
(HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies
(HCAb)
[21] Phase 2 only: Endocrine pancreatic tumors or ampullary cancer.
[22] Phase 1: Patients with acute or chronic leukemia or with any other
disease likely to have a significant bone marrow infiltration
[23] Have previously completed or withdrawn from this study or any other
study investigating LY2603618 or any other Chk-1 inhibitor.
[24] Have known allergy to gemcitabine or LY2603618 or any ingredient
of gemcitabine or LY2603618.
[25] Has an abnormal ECG result that would put the patient at unnecessary
risk in the opinion of the investigator.
[26] Have conduction abnormalities, ischemic changes such as prior Qwave
myocardial infarction and/or marked ischemic ST and T wave,
and arrhythmias such as persistent or paroxysmal ventricular or
supraventricular arrhythmias, including atrial fibrillation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: The primary endpoint is establishing the maximum tolerated dose or biological active dose based on pharmacokinetics for LY2603618 when administered 24 hours after gemcitabine therapy.
Phase II: OS in patients with stage II-IV unresectable pancreatic cancer who received LY2603618 and gemcitabine combination arm compared to OS on the gemcitabine only.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 9 months after 99th patient enrolled |
|
| E.5.2 | Secondary end point(s) |
The secondary objectives of Phase 1 are:
To characterize the preliminary safety and toxicity profile of LY2603618
when administered after gemcitabine.
To evaluate the preliminary PKs of gemcitabine, deoxydifluorouridine
(dFdU) and LY2603618 in combination.
To document any antitumor activity observed after administration of
LY2603618 and gemcitabine.
To explore biomarker responses associated with LY2603618 and
gemcitabine combination:
Incorporation of nucleoside analogs (for example, gemcitabine) into
the DNA of peripheral blood cells.
Detection of fragmented cytokeratin 18 cleaved at Asp396 (M30
neoantigen).
To perform an initial assessment of the potential effect of LY2603618 on QTc prolongation.
The secondary objectives of the Phase 2 are:
To characterize further the safety and toxicity profile of LY2603618 when administered after gemcitabine and to compare it to the safety profile of gemcitabine monotherapy in the advanced pancreatic cancer population.
To estimate other time-to-event variables, such as PFS and duration of
response.
To explore the percentage change in tumor size at 8 weeks and the
relationship with OS.
To document response rate per Response Evaluation Criteria in Solid
Tumors (RECIST Version 1.1).
To evaluate the pharmacokinetics of gemcitabine, deoxydifluorouridine
(dFdU) and LY2603618 in combination.
To assess biomarker responses associated with LY2603618 and
gemcitabine combination:
Incorporation of nucleoside analogs (for example, gemcitabine) into
the DNA of peripheral blood cells.
Detection of p53 in tumor tissue.
Detection of fragmented cytokeratin 18 cleaved at Asp396 (M30
neoantigen).
To explore the evolution of CA19.9 in patients with pancreatic cancer
for each treatment group and its relation with efficacy parameters.
To explore the pharmacogenetic of drug metabolism enzyme and
transporter (DMET) polymorphisms and its relation with the PK
profile, safety and efficacy.
To perform an exploratory assessment of QTc. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 9 months after 99th patient enrolled will be the final analysis of the study; however, patients may continue on study until progression or other reason for discontinuation which may be longer than 9 months after the 99th patient is enrolled. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 1 is not randomized. Phase 2 is randomized for pancreatic patients specific |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Slovakia |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The primary endpoint of the Phase 1 was to determine the MTD and the Phase 2 dose.
The primary endpoint of Phase 2 will be determining the overall survival of the study treatment compared to control arm. Patients will be followed approximately every 60 days until death or study ends. The final analysis of the study will occur 9 months after the 99th patient has enrolled. Patient may continue on study as long as they are benefitting at the discretion of the investigator. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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