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Lung Non-Small Cell CarcinomaPhase 1/2NCT05022394

Sapanisertib and Nivolumab for the Treatment of Stage I-IV Non-small Cell Lung Cancer in Patients Who Have Progressed on Prior PD-1/PD-L1 Inhibitor Therapy, I-OVERCOME Study

A Phase 1/2 study testing Nivolumab and Sapanisertib in people with Lung Non-Small Cell Carcinoma and Recurrent Lung Non-Small Cell Carcinoma, run by M.D. Anderson Cancer Center.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This phase I/II trial studies the side effects of sapanisertib and nivolumab and to see how well they work in treating patients with stage I-IV non-small cell lung cancer whose disease got worse on previous PD-1/PD-L1 inhibitor therapy. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab and Sapanisertib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
18 Feb 2021to 18 Feb 2021
Phase
Phase 1/2
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

  • Patients with stage IV non-small cell lung cancer with disease progression on or up to 6 months from treatment with PD-1/PD- L1 inhibitor either alone or in combination with chemotherapy and/or anti-CTLA4 inhibitor; or patients with stage I-III non-small cell lung cancer with disease recurrence up to 6 months from receiving neoadjuvant/adjuvant/consolidation PD-1/PD-L1 inhibitor
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • All immune-related adverse events (AEs) while receiving prior immunotherapy must have resolved to grade =< 1 prior to screening for the study. Patients with endocrine immune-related AE of =< grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy
  • Female patients who:
  • Are postmenopausal for at least 1 year before the screening visit, OR
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  • Are surgically sterile, OR
  • If they are women of childbearing potential (WOCBP), agree to practice 1 effective method of contraception and 1 additional effective (barrier) method, at the same time, and must agree to follow instructions for methods of contraception from the time of signing the informed consent, for the duration of treatment with nivolumab and 5 months after the last dose of nivolumab (ie 30 days [duration of ovulatory cycle] plus the time required for nivolumab to undergo approximately five half-lives), OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  • Agree not to donate egg(s) during the course of this study or within 5 months after the last dose of nivolumab (ie 30 days [duration of ovulatory cycle] plus the time required for nivolumab to undergo approximately five half-lives)
  • Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
  • Are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab and up to 7 months after the last dose of nivolumab (ie 90 days [duration of sperm turnover] plus the time required for nivolumab to undergo approximately five half-lives)., OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together)
  • Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without transfusion within 1 week preceding study drug administration
  • Platelet count >= 100 x 10^9/L without transfusion within 1 week preceding study drug administration
  • Hemoglobin >= 9 g/dL without transfusion within 1 week preceding study drug administration
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) =< 2.5 x ULN (=< 3 x ULN if liver metastases are present)
  • Clearance >= 50 mL/min based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour)
  • Glycosylated hemoglobin (HbA1c) < 7.0%
  • Fasting serum glucose (=< 130 mg/dL)
  • Fasting triglycerides =< 300 mg/dL
  • Ability to swallow oral medications
  • Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
  • Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
  • Brain metastases which have been previously treated and/or are stable on most recent brain imaging
  • Systemic corticosteroids at physiological doses, which are not to exceed 10mg/day of prednisone, or an equivalent corticosteroid

Who cannot join

  • Histology other than non-small cell lung cancer
  • Central nervous system (CNS) metastasis that is symptomatic and uncontrolled
  • Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
  • Presence of an EGFR, ALK, and ROS1 alteration
  • Current systemic anti-cancer treatment other than the study agents, including other investigational agents
  • Previous toxicity that led to permanent and indefinite discontinuation of prior immunotherapy
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  • Toxicity from prior immunotherapy required the use of additional immunosuppression other than corticosteroids for management of the AE
  • Experienced recurrence of grade >= 3 immune-related AE if re-challenged with immunotherapy. Patients with endocrine immune-related AE of =< grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy
  • Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
  • Known human immunodeficiency virus infection
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Concurrent malignancy with evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • Breast feeding or pregnant women
  • Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors
  • Current or prior use of immunosuppressive medication within 28 days before cycle 1 of study treatment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Active or prior documented autoimmune disease within the past 2 years
  • NOTE: vitiligo, alopecia, chronic skin condition that does not require systemic therapy, psoriasis not requiring systemic treatment (within the past 2 years), and hypothyroidism (if stable on hormonal therapy) are not exclusion criteria
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or pneumonitis
  • Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of sapanisertib. In addition, patients with enteric stomata are also excluded
  • Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fredericia (QTcF) prolongation > 480 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome or torsade de pointes
  • History of any of the following within the last 6 months before administration of the first dose of the drug:
  • Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
  • Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
  • Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
  • Placement of a pacemaker for control of rhythm;
  • New York Heart Association (NYHA) class III or IV heart failure
  • Pulmonary embolism
  • Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of study treatment and patients must have recovered from any effects of any major surgery. Note: Local surgery of isolated lesions for palliative intent is acceptable
  • Uncontrolled illness including, but not limited to, ongoing or active infection, seizures, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, pulmonary hypertension, uncontrolled asthma or oxygen (O2) saturation =< 90% by arterial blood gas analysis or pulse oximetry in room air, cardiac valve disease, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >= 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met
  • Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study
  • Patients who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug
  • Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing two highly effective methods of birth control
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Known allergy or hypersensitivity to nivolumab, sapanisertib or any excipients
  • Any persistent toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with sapanisertib and/or nivolumab may be included at physician discretion

About this study

Official title: Phase I/II Study to OVERCOME Resistance to PD-1/PD-L1 Inhibitor Immunotherapy in Advanced Non-Small Cell Lung Cancer - I-OVERCOME Trial

This phase I/II trial studies the side effects of sapanisertib and nivolumab and to see how well they work in treating patients with stage I-IV non-small cell lung cancer whose disease got worse on previous PD-1/PD-L1 inhibitor therapy. Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sapanisertib and nivolumab may help to control the disease.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the toxicity of the combination of sapanisertib and nivolumab in patients with advanced non-small cell lung cancer (NSCLC) who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

II. To confirm recommended phase 2 dose (RP2D) of the combination of sapanisertib and nivolumab in patients with advanced NSCLC who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

III. To estimate the objective response rate of the combination of sapanisertib and nivolumab in patients with advanced NSCLC who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

SECONDARY OBJECTIVES:

  1. To determine progression free survival (PFS) of the combination of sapanisertib and nivolumab in patients with advanced NSCLC who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

II. To determine overall survival (OS) of the combination of sapanisertib and nivolumab in patients with advanced NSCLC who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

III. To estimate the disease control rate of the combination of sapanisertib and nivolumab in patients with advanced NSCLC who have had disease progression on prior PD-1/PD-L1 inhibitor therapy.

IV. To determine if there are drug-drug interaction (DDI) for the combination of sapanisertib and nivolumab.

EXPLORATORY OBJECTIVES:

  1. To compare gene and protein expression in pre-treatment and on-treatment tumor samples.

II. To compare gene and protein expression in tumor samples of responders and nonresponders.

III. To compare immune cell infiltration and immune markers in pre-treatment and on-treatment tumor samples.

IV. To compare immune cell infiltration and immune markers in tumor samples of responders and non-responders.

  1. To correlate clinical outcomes with tumor mutational burden and cancer gene mutations detected by molecular profiling.

VI. To compare gene expression at the single-cell level in pre-treatment and on-treatment tumor samples.

VII. To compare gene expression at the single-cell level in tumor samples of responders and non-responders.

VIII. To compare cell-free deoxyribonucleic acid (DNA) levels in pre-treatment, on-treatment, and at progression tumor samples.

OUTLINE:

Patients receive sapanisertib orally (PO) once daily (QD) on days 1, 8, 15, and 22 and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Being tested
Nivolumab, Sapanisertib
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Lung Neoplasms

What participants receive

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

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

  • SapanisertibDrug

    Also called INK-128, INK128, MLN-0128, MLN0128

    Given PO

Study groups in NCT05022394
Study groupRoleWhat they receive
Treatment (sapanisertib, nivolumab)ExperimentalPatients receive PO QD on days 1, 8, 15, and 22 and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Biological: Nivolumab; Drug: Sapanisertib

What is being measured

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

  1. Objective response rate (ORR)

    Will be measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Objective response rate will be calculated as the number of responders divided by the number of evaluable patients along with a 90% confidence interval. The ORR by dose level will also be evaluated.

    Measured: Cycle 1 through Cycle 4 (each cycle is 28 days)

  2. Incidence of dose limiting toxicity (DLT)

    Dose Limiting Toxicity will be measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Toxicity data will be tabulated using frequency and percentage by type, grade, and attribution.

    Measured: Cycle 1 through Cycle 4 (each cycle is 28 days)

Secondary outcomes (5)

  1. Progression-free survival (PFS)

    The Kaplan-Meier method will be used to estimate the distribution of PFS. Median survival time (if estimable), along with the two sided 95% confidence interval (CI) will be presented. When appropriate, univariate or multicovariate Cox proportional hazards regression will be employed to explore the significances of factors on survival.

    Measured: From enrollment until progression or death, assessed up to 16 months

  2. Overall survival (OS)

    The Kaplan-Meier method will be used to estimate the distribution of OS. Median survival time (if estimable), along with the two sided 95% CI will be presented. When appropriate, univariate or multicovariate Cox proportional hazards regression will be employed to explore the significances of factors on survival.

    Measured: From enrollment until death by any cause, assessed up to 16 months

  3. Disease control rate

    Will be measured by RECIST v1.1. Disease control will be defined as CR/PR/SD post-cycle 4; absence of disease control will be defined as PD within 4 cycles of study treatment.

    Measured: Cycle 1 through Cycle 4 (each cycle is 28 days)

  4. Maximum serum concentration of sapanisertib (Cmax)

    Measured: Up to 16 months

  5. Area under the plasma drug concentration-time curve (AUC)

    Defined as definite integral in a plot of drug concentration in blood plasma versus time.

    Measured: Up to 16 months

Timeline

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

  1. First posted26 Aug 2021
  2. Study start18 Feb 2021
  3. Primary completion18 Feb 2021
  4. Study completion18 Feb 2021

Why it stopped: No participants Enrolled

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05022394
Sponsor's protocol ID
2019-1262
Other IDs
NCI-2020-02356, 2019-1262
Status last verified
May 2022
First submitted
22 Apr 2020
Last updated
27 May 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Nivolumab and Sapanisertib in people with Lung Non-Small Cell Carcinoma and Recurrent Lung Non-Small Cell Carcinoma, run by M.D. Anderson Cancer Center.

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 28 inclusion and 39 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: withdrawn, as of the sponsor's last update on 27 May 2022. Status can change between updates, so confirm with the study contact before making plans.

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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 was withdrawn before enrolling participants, so there are no results.

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?

Objective response rate (ORR) (time frame: Cycle 1 through Cycle 4 (each cycle is 28 days)). The study lists 2 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 NCT05022394.

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 27 May 2022.

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