A Dose Escalation Study of Adavosertib (MK-1775) in Combination With Either Gemcitabine, Cisplatin, or Carboplatin in Adults With Advanced Solid Tumors (MK-1775-001)

Solid Tumors Clinical Trial

Official title:

A Phase I Dose Escalation Study Evaluating MK-1775 in Both Monotherapy and in Combination With Either Gemcitabine, Cisplatin, or Carboplatin in Adult Subjects With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00648648
• Other study ID #: 1775-001
• Secondary ID: 2007_611MK-1775-
• Status: Completed
• Phase: Phase 1
• Start date: February 25, 2008
• Est. completion date: January 6, 2014

Study information

• Verified date: August 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will investigate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) activity of adavosertib, both as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in participants with advanced solid tumors. Dose limiting toxicities (DLT) of adavosertib in combination with gemcitabine, cisplatin, or carboplatin will also be assessed. The primary hypotheses of the study are as follows: 1) Oral administration of adavosertib both as monotherapy and in combination with either gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors will be safe and tolerable, 2) The side effects observed in participants with advanced solid tumors after administration of adavosertib combined with each of the chemotherapies (gemcitabine, cisplatin and carboplatin) will allow for the definition of a single dose combination Maximum Administered Dose (MAD)/Maximum Tolerated Dose (MTD) and a multiple dose combination Biologically Effective Dose (BED)/MTD for each of the 3 combinations, 3) At a tolerated dose, adavosertib plasma exposure will exceed target thresholds established in preclinical models, and 4) At a tolerated dose, PD markers of adavosertib activity in combination with either gemcitabine, cisplatin, or carboplatin (in surrogate tissue and/or tumor) will meet or exceed the target threshold established in preclinical models.

Description:

Part 1 consists of single dose adavosertib monotherapy. If well tolerated, participants in Part 1 will continue on to one of three treatment arms in Part 2-A which consists of a single lower dose of adavosertib in combination with standard chemotherapy: 1) Adavosertib +Gemcitabine (1000 mg/m^2), 2) Adavosertib + Cisplatin (75 mg/m^2) or 3) Adavosertib +Carboplatin at an area under the time curve concentration of 5 mg/min/ml (AUC5). Following completion of Part 2-A, adavosertib will be administered twice daily (BID) for 2.5 days (multi-dose) starting concomitantly with each administration of chemotherapy in Part 2-B. After a preliminary combination MTD of adavosertib and chemotherapy has been established in Part 2B, the MTD confirmation expansion will occur in Part 3.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 206
• Est. completion date: January 6, 2014
• Est. primary completion date: January 6, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Must have a histologically confirmed metastatic or locally advanced solid tumor, progressed despite standard therapy, or for which standard therapy does not exist
• Must have performance status of <=1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Female participants must not be pregnant

Exclusion Criteria:

• Has had chemotherapy, radiotherapy, or biological therapy within 4 weeks prior to entering the study or who has not recovered from adverse events due to agents given more than 4 weeks earlier
• Is participating or has participated in a study with an investigational compound or device within 30 days
• Has active central nervous system (CNS) metastases and/or carcinomatous meningitis. However, participants with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for 1 month prior to entry
• Has a primary central nervous system tumor
• Is allergic to any of the components of the combination study therapy or its analogs
• Participant has had prescription or non-prescription drugs or other products known to be metabolized by Cytochrome P450 3A4 (CYP3A4) that cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication. Medications of particular concern are inhibitors of CYP3A4 (azole antifungals [ketoconazole, itraconazole], macrolide antibiotics [erythromycin, clarithromycin], cimetidine, aprepitant, Human Immunodeficiency Virus (HIV) protease inhibitors, nefrazodone, and the following inducers of CYP3A4: phenytoin, barbiturates and rifampicin, and substrates of CYP3A4 including statins (lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride
• Is a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse
• Pregnant or breastfeeding, or expecting to get pregnant during the time the study will be ongoing
• HIV-positive
• History of Hepatitis B or C
• Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions is eligible
• Participant must not have prior radiation therapy to more than 30% of the bone marrow and must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy
• Has had a prior stem cell or bone marrow transplant
• Has received more than 4 prior cytotoxic chemotherapy regimens
• Has a history suggestive of Li-Fraumeni Syndrome

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• adavosertib
adavosertib administered as an oral formulation as either monotherapy or in combination with either gemcitabine, cisplatin, or carboplatin.
• gemcitabine
Gemcitabine administered at 1000 mg/m^2 by IV infusion in a 28-day cycle.
• cisplatin
Cisplatin administered at 75 mg/m^2 by IV infusion in a 21-day cycle.
• carboplatin
Carboplatin administered at AUC/time curve of 5 mg/min/mL (AUC5) by IV infusion in a 21-day cycle.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)	DLTs were adverse events (AEs) considered at least possibly related to study drug that prevented escalation of the drug dose. Hematologic DLTs were any grade (Gr) 4-5 toxicity EXCEPT: Gr 4 anemia and Gr 4 leukopenia, Gr 4 neutropenia lasting for <7 days, Gr 4 thrombocytopenia lasting for <4 days except if a platelet transfusion is required, and Gr 3/Gr 4 neutropenia with fever >38.5°C and/or infection requiring antibiotic or anti-fungal treatment. Non-hematologic DLT was defined as any Gr 3, 4, or 5 non-hematologic toxicity EXCEPT: nausea, vomiting, diarrhea, or dehydration (all Gr 3) occurring in a setting of inadequate compliance with supportive care measures and lasting for <48 hours, alopecia of any grade, inadequately treated hypersensitivity reactions, and clinically non-significant, treatable or reversible lab abnormalities including liver function tests, uric acid, etc.	Part 1: Up to 14 days, Part 2: Up to 28 days
Primary	Percentage of Total Cyclin-dependent Kinase (CDC2)-Positive Cells That Were Phosphorylated (pCDC2) in Skin Cells at Baseline and 8 Hours After MK-1775 Dosing	The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total CDC2-positive cells that were pCDC2 positive (% pCDC2-positive cells) at baseline and 8 hours after MK-1775 dosing were reported for participants in Part 1, 2-A, and 2-B/3 treatment groups with available data per protocol.	Baseline, 8 hours after first MK-1775 dose
Primary	Percentage of Total pCDC2 in Skin Cells at Baseline and 24 Hours After MK-1775 Dosing	The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total pCDC2 at baseline and 24 hours after MK-1775 dosing were reported for participants in the Part 2-B/3 MK-1775 QD x2 Multi Dose plus Gemcitabine treatment groups with available data per protocol.	Baseline, 24 hours after first MK-1775 dose
Primary	Percentage of Total pCDC2 in Skin Cells at Baseline and 48 Hours After MK-1775 Dosing	The pCDC2 level in skin cells was used as a marker to evaluate MK-1775 activity. Analysis was done by immunohistochemistry and the percentage of total pCDC2 at baseline and at 48 hours after MK-1775 dosing were reported for participants in the Part 2-B/3 MK-1775 (150 mg, 200 mg, 250) BID x 2.5 Multi Dose plus cisplatin 75 mg/m^2 groups and the 325 mg BID x2.5 Multi Dose + Carboplatin group with available data per protocol.	Baseline, 48 hours after first MK-1775 dose
Primary	Plasma Concentration of MK-1775 at 8 Hours After Administration (C8hr) of Single or Multiple Oral Doses	MK-1775 was measured in the plasma at 8 hours after dosing (Day 1 for single dose of monotherapy, Day 2 of single-dose combination therapy and QD x 2 Combination dosing, and Day 3 dose for BID X 2.5 combination dosing) for participants with available data.	8 hours after MK-1775 dose
Primary	Mean Urine Excretion of MK-1775 24 Hours After the Day 1 Monotherapy Dose	The mean cumulative amount of MK-1775 excreted unchanged in urine after a single oral dose was measured during the initial monotherapy cycle of the study. For this outcome measure, samples were collected and analyzed only for the MK-1775 monotherapy arms of the study at defined intervals after the Day 1 dose of monotherapy. Part 2 MK-1775 combination arms were not sampled per protocol.	At 0-4 hours, 4-8 hours, and 12-24 hours post Day 1 dose of monotherapy
Secondary	Best Overall Response as Per Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	Best overall response achieved by a participant. Starting at Day 1, participants in Part 2 were evaluated for tumor response every 6-8 weeks until discontinuation from study treatment according to RECIST criteria; which are based on radiographic imaging. Recorded responses were either confirmed by Central Review or unconfirmed (Investigator assessment only), and included complete response (CR; defined as disappearance of all target lesions), partial response (PR; at least a 30% decrease in the sum of the longest diameter [LD] of target lesions, taking as reference the baseline sum LD), stable disease (SD; neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD, taking as reference the smallest sum LD since the treatment started), or progressive disease (PD; =20% increase in sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions).	From Day 1 up through discontinuation of study treatment (up to ~11.2 months)

External Links

•   Merck Clinical Trials Information