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CancerPhase 1NCT02240212

Study of Afuresertib Combined With Paclitaxel in Gastric Cancer

A Phase 1 study testing Afuresertib and Paclitaxel in people with Cancer, run by Novartis Pharmaceuticals at 5 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Cancer
What is being tested?
Afuresertib and Paclitaxel
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
5 sitesin 2 countries
Study dates
Oct 2014to 7 Feb 2017
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • Metastatic or locally advanced, unresectable disease.
  • Subjects must have received first-line platinum/fluoropyrimidine doublet regimen for advanced gastric cancer and now exhibit progressive disease (PD), and must have recovered from any treatment-related toxicity. Note: prior XELOX, XP, FOLFOX, or SP (S-1+cisplatin)) treatment could be eligible, but prior-taxane are ineligible. Note: if patient is refractory or disease progression within 6 months of adjuvant treatment, then his previous treatment would be considered as first line treatment rather than adjuvant treatment, and then this patient could be enrolled into this study if other inclusion/exclusion criterion meets.
  • Subjects shall have at least one measurable disease (i.e., present with at least one measurable lesion) by RECIST version1.1

Who cannot join

  • 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.
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  • 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.
  • Any history of reduction in standard of care paclitaxel dose for peripheral neuropathy.
  • Known Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C. (Note: active Hepatitis B virus (HBV) infection is defined as ALT/AST is above or equal to normal range or HBV deoxyribonucleic acid (DNA) >=2×10^3-4 international unit (IU)/mL; active Hepatitis C virus (HCV) infection is defined as HCV ribonucleic acid (RNA)+ and ALT/AST is above normal range). Antiviral therapy should be initiated before study treatment, and maintain during study treatment in patients with inactive HBV infection. Prophylaxis against HBV reactivation is recommended in accordance with established guidelines: the Asian-Pacific census statement on HBV in 2012 and Taiwan health insurance guidance in 2013.

Trial locations and contacts

5 sites in 2 countries.

5 sites in 2 countries

South Korea3 sites

  • Novartis Investigative Site

    Seoul, 110-774

  • Novartis Investigative Site

    Seoul, 120/752

  • Novartis Investigative Site

    Seoul, 135-710

Other trials in South Korea

Taiwan2 sites

  • Novartis Investigative Site

    Taipei, 100

  • Novartis Investigative Site

    Taipei, 112

Other trials in Taiwan

About this study

Official title: Phase Ib Study of Afuresertib Combined With Paclitaxel in Pre-treated HER2-negative Advanced Gastric Cancer

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
Being tested
Afuresertib, Paclitaxel
Keywords
second line treatment, oncology, AKT inhibitor, paclitaxel, HER2 (ErbB2) negative advanced gastric cancer, Afuresertib
Medical subject headings
Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AfuresertibDrug

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

  • PaclitaxelDrug

    Paclitaxel sourced locally will be administered IV

Study groups in NCT02240212
Study groupRoleWhat they receive
Part 1: Dose-escalation (weekly paclitaxel)ExperimentalThe 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
Receives: Drug: Afuresertib; Drug: Paclitaxel
Part 1: Dose-escalation (3 weeks Paclitaxel)ExperimentalOnce 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
Receives: Drug: Afuresertib; Drug: Paclitaxel
Part 2: Experimental CohortExperimentalThe optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be administered
Receives: Drug: Afuresertib; Drug: Paclitaxel

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

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

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

    Clinical laboratory tests included hematology, clinical chemistry, urinalysis

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

  3. 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

    Measured: Screening and Day 22

  4. 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)

    Measured: 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)

  5. 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

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

  6. 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

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

  7. 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.

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

  8. 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.

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

Secondary outcomes (7)

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

    Afuresertib pharmacokinetic parameters following single and repeat dose administration, including Area under the concentration-time curve (AUC), Maximum observed concentration (Cmax) and paclitaxel Pre-dose (trough) concentration at the end of the dosing interval (Ctrough), Cmax after repeat dose administration, time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2)

    Measured: 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

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

    PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause by investigator assessment

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

  3. Number of subjects with any SAE, AE in expansion cohort

    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

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

  4. Assessment of changes in clinical laboratory tests in expansion cohort

    Clinical laboratory tests included hematology, clinical chemistry, urinalysis

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

  5. Assessment of 12-lead ECG findings in expansion cohort

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

    Measured: Screening and Day 22

  6. Assessment of ECHOs in expansion cohort

    The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs The evaluation of the echocardiographer should include an evaluation LVEF

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

  7. Assessment of composite pharmacokinetics of afuresertib and paclitaxel in expansion cohort

    Afuresertib concentration following single and repeat dose administration and Paclitaxel Ctrough and Cmax after repeat dose administration

    Measured: 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 Day 1 (pre-dose, 1 to 3 h), Day 15 (pre-dose, 1 to 3 h and 6-8 h) for weekly dose Paclitaxel regimen

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Sep 2014 (estimated)
  2. Study startOct 2014
  3. Primary completion7 Feb 2017
  4. Study completion7 Feb 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02240212
Sponsor's protocol ID
201050
Status last verified
Apr 2017
First submitted
11 Sep 2014
Last updated
11 Apr 2017
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Afuresertib and Paclitaxel in people with Cancer, run by Novartis Pharmaceuticals at 5 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in South Korea, Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of subjects with any serious adverse event (SAE), non-serious adverse event (AE) in Phase I Dose Escalation phase (time frame: Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02240212.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Apr 2017.

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