Study of Afuresertib Combined With Paclitaxel in Gastric Cancer

NCT02240212 | Completed Phase 1

• 1 other identifier: 201050
• Study Type: interventional
• Target: 29
• Locations: 2 countries
• Sites: 5

Brief Summary

This is a Phase Ib, open-label, dose-escalation study to determine the Maximal tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for the combination of afuresertib and paclitaxel in subjects with recurrent HER2-negative gastric cancer, and further assess safety and preliminary efficacy of combination at the RP2D. Afuresertib had showed synergistic activity when combined with paclitaxel in vitro and in vivo models of gastric cancer. Dose escalation will continue until the MTD is established. The dose schedule is once daily (QD) dosing for afuresertib and intravenous (IV) infusion for paclitaxel Dose escalation in Part 1 will follow the 3 + 3 cohort design. A sequential approach will be conducted to explore the optimal paclitaxel regimen (weekly or 3weekly schedule) when combined with afuresertib. The dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel regimen at 80 milligram (mg)/meter (m)\^2 day1, 8,15, every 4 weeks (q4w). The starting dose in Cohort A will be 125 mg afuresertib QD. Once its MTD is identified, and then the study will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m\^2 day1, every 3 week (q3w). The starting daily dose of Cohort B will be 25 mg less than the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the starting dose is not tolerated, then dose de-escalation will be explored until the MTD in this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be identified. The combination regimen at the RP2D selected following Part I will be further investigated in its efficacy and safety in the Part II Expansion Cohort. Once a combination dose regimen for Part 2 has been determined, at least 20 and up to 40 subjects will be enrolled at the dose regimen selected following Part I. Overall response rate (ORR) will be evaluated using a Green-Dahlberg design. The design consists with one interim analysis. If less than 3 responses are observed in the initial 20 subjects, enrollment will be terminated due to futility; otherwise, the study will continue to meet the planned sample size of 40 subjects.

Conditions

Cancer

Keywords

second line treatment; oncology; AKT inhibitor; paclitaxel; HER2 (ErbB2) negative advanced gastric cancer; Afuresertib

Outcome Measures

Primary Outcomes (8)

• Number of subjects with any serious adverse event (SAE), non-serious adverse event (AE) in Phase I Dose Escalation phase

  An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect

  Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)

• Assessment of changes in clinical laboratory tests in Phase I Dose Escalation phase

  Clinical laboratory tests included hematology, clinical chemistry, urinalysis

  Day 1 to Day 21 after the last dose of study treatment. (assessed up to 1 years)

• Assessment of 12-lead electrocardiogram (ECG) findings in Phase I Dose Escalation phase

  Heart rate, pulse rate (PR), QRS, QT, and Electrocardiogram QT interval corrected for heart rate using Fridericia's formula (QTcF intervals) will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-recumbent or supine position after 5 minutes rest

  Screening and Day 22

• Assessment of Echocardiograms (ECHOs) in Phase I Dose Escalation phase

  The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs. The evaluation of the echocardiographer should include an evaluation for left ventricular ejection fraction (LVEF)

  Every 9 weeks (for 3 weekly paclitaxel regimen) and every 8 weeks (for weekly paclitaxel regimen) until day 21 after last dose of study treatment (assessed up to 1 years)

• Assessment of blood pressure (vital signs) in Phase I Dose Escalation

  Vital signs will include measurement of systolic and diastolic blood pressure. Vital signs should be measured after resting for at least 5minutes in a semi-supine position

  Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)

• Assessment of preliminary clinical efficacy in Phase II dose expansion

  Tumor response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST 1.1), the ORR will be based on confirmed responses by investigator-based assessment for gastric cancer

  Every 6 weeks for 3 weekly paclitaxel regimen or every 8 weeks for weekly paclitaxel regimen (assessed up to 1 years)

• Assessment of respiration rate (vital signs) in Phase I Dose Escalation

  Vital signs will include measurement of respiration rate. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.

  Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]

• Assessment of PR (vital signs) in Phase I Dose Escalation

  Vital signs will include measurement of PR. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.

  Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]

Secondary Outcomes (7)

• Composite of pharmacokinetics parameters of afuresertib and paclitaxel combination regimen in dose escalation cohort

  Day 1 (pre-dose, 1 to 3 hour [h]), Day 22 (pre-dose, 1 to 3 h and 6-8 h) for 3 weekly dose Paclitaxel regimen

• Evaluation of the progression free survival (PFS) in expansion cohort

  Day 1and the earliest date of disease progression or death due to any cause; up to 6 months

• Number of subjects with any SAE, AE in expansion cohort

  Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years).

• Assessment of changes in clinical laboratory tests in expansion cohort

  Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)

• Assessment of 12-lead ECG findings in expansion cohort

  Screening and Day 22

Study Arms (3)

Part 1: Dose-escalation (weekly paclitaxel)

EXPERIMENTAL

The dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel regimen at 80 mg/m\^2 d1, 8,15, q4w). The starting dose in Cohort A will be 125 mg afuresertib QD to indentify MTD

Drug: Afuresertib; Drug: Paclitaxel

Part 1: Dose-escalation (3 weeks Paclitaxel)

EXPERIMENTAL

Once its MTD is identified, and then the study will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m\^2 d1, q3w. Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m\^2 d1, q3w). The starting daily dose of Cohort B will be 25 mg less than the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the starting dose is not tolerated, then dose de-escalation will be explored until the MTD in this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be identified

Drug: Afuresertib; Drug: Paclitaxel

Part 2: Experimental Cohort

EXPERIMENTAL

The optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be administered

Drug: Afuresertib; Drug: Paclitaxel

Interventions

Afuresertib DRUG

The unit dose strength is 50mg/75mg tablet. Afuresertib will be taken orally once daily continuously during trail.

Part 1: Dose-escalation (3 weeks Paclitaxel); Part 1: Dose-escalation (weekly paclitaxel); Part 2: Experimental Cohort

Paclitaxel DRUG

Paclitaxel sourced locally will be administered IV

Part 1: Dose-escalation (3 weeks Paclitaxel); Part 1: Dose-escalation (weekly paclitaxel); Part 2: Experimental Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provided signed written informed consent
• Male or female \>=18 years of age with a diagnosis of Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology at the time of signing the informed consent
• Able to swallow and retain orally administered study treatment
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception during the study. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception (Condom \[during non-vaginal intercourse with any partner - male or female\] OR Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) \[during sexual intercourse with a female\]. Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Adequate organ system functions at screening as Hematologic system (Absolute neutrophil count \>=1.5 x 10\^9/Litre (L), Hemoglobin \>=9.0 gram (g)/deci (d)L, Platelets \>=100 x 10\^9/microL without transfusion in the past 7 days, prothrombin time/ international normalized ratio (PT/INR) and partial thromboplastin time (PTT) \<=1.5 x Upper limit of normal \[ULN\]), Hepatic system (Total bilirubin \<=1.0x ULN, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<=2.5x ULN), Metabolic system (Fasting Serum Glucose \< 126 milli (m)g/dL \[7 millimol/L\], Hemoglobin A1C\<=8%) and Renal system (Serum creatinine \<= ULN, 24-hour urine creatinine clearance \>=60 mL/minute \[min\])
• Histologically confirmed from the stomach or gastroeosophageal (GE) junction cancer with documented HER2-negative (defined as immunohistochemistry (IHC) 0-1+ or IHC2+ with a negative fluorescent in situ hybridization (FISH) test assessed by local or designated central lab) in primary or metastatic tumor tissue.
• Metastatic or locally advanced, unresectable disease.
• Subjects shall have at least one measurable disease (i.e., present with at least one measurable lesion) by RECIST version1.1

You may not qualify if:

• History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
• Prior PI3K-AKT- mammalian target of rapamycin (mTOR) pathway targeted therapy will not be eligible. (Note: prior vaccine and immunotherapy is allowed but must end at least 8 weeks prior to study treatment).
• Unresolved toxicity (Grade \<=1) from prior chemotherapy with the exception of alopecia or anemia (Hemoglobin \>9 g/dL).
• Subjects with uncontrolled brain metastases or spinal cord compression.
• Current use of warfarin for therapeutic anticoagulation (Note: low molecular weight heparin is permitted).
• Presence of an active gastrointestinal disease (not including gastric cancer), or other condition known to interfere significantly with the absorption, distribution, metabolism, or excretion of drugs. Prior gastrectomy is allowed.
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening.
• Pregnant or lactating female.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Any prohibited medication(s) as Co-administration of afuresertib and medications which are a sensitive substrate of CYP3A4, OATP1B1 and BCRP with a low therapeutic index will be prohibited. Coadministration of afuresertib and medications which are a sensitive substrate of CYP2C8 with a low therapeutic index will be used with caution.
• History of Type 1 diabetes
• Any major surgery within the last four weeks.
• QTcF interval \>=470 milliseconds (msec)s.
• known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar or related to afuresertib and taxanes.
• Any contraindications (as identified by the investigator) to the doses of paclitaxel defined in the protocol.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (5)

Novartis Investigative Site

Seoul, 110-774, South Korea

Location

Novartis Investigative Site

Seoul, 120/752, South Korea

Location

Novartis Investigative Site

Seoul, 135-710, South Korea

Location

Novartis Investigative Site

Taipei, 100, Taiwan

Location

Novartis Investigative Site

Taipei, 112, Taiwan

Location

MeSH Terms

Conditions

Neoplasms

Interventions

afuresertib; Paclitaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2014
• First Posted: September 15, 2014
• Study Start: October 1, 2014
• Primary Completion: February 7, 2017
• Study Completion: February 7, 2017
• Last Updated: April 11, 2017

Record last verified: 2017-04

Locations

KR (3); TW (2)