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A Study of CC-90010 in Combination With Temozolomide With or Without Radiation Therapy in Subjects With Newly Diagnosed Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04324840
Recruitment Status : Not yet recruiting
First Posted : March 27, 2020
Last Update Posted : April 30, 2020
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

Study CC-90010-GBM-002 is for newly diagnosed WHO Grade IV glioblastoma to determine the safety and tolerability and evaluate escalating doses of the investigational drug CC-90010 when combined with standard of care treatment temozolomide (TMZ) with or without radiotherapy (RT).

The standard of care for ndGBM includes surgical resection to the extent that is safely feasible, followed by RT plus concomitant TMZ chemotherapy, and up to 6 months of adjuvant TMZ. The study also aims to determine whether the addition of CC-90010 can control the disease.


Condition or disease Intervention/treatment Phase
Glioblastoma Drug: CC-90010 Drug: Temozolomide Phase 1 Phase 2

Detailed Description:

The dose escalation part (Part A) of the study will initially explore escalating oral doses of CC-90010 in combination with adjuvant TMZ to estimate the MTD (Maximum tolerated dose) and/or the RP2D (recommended Phase 2 Dose) of CC-90010 as adjuvant therapy. After two dose escalation levels (or earlier as decided by the Safety Review Committee ) are assessed as safe and tolerated in the Adjuvant Therapy dose escalation, the Concomitant Therapy dose escalation will start, exploring escalating oral doses of CC-90010 in combination with concomitant TMZ+RT, to estimate the MTD and/or the RP2D of CC-90010 as concomitant therapy.

The expansion part (Part B) will further evaluate the safety and efficacy of CC-90010 administered at or below the MTD determined for the Adjuvant Therapy and the Concomitant Therapy in Part A, in expansion cohorts of approximately 20-30 evaluable subjects each, in order to further define the RP2D. Parts A and B will consist of three periods: Screening, Treatment, and Follow-up periods.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b, Open-label, Dose-Finding Study of CC-90010 in Combination With Temozolomide With or Without Radiation Therapy in Subjects With Newly Diagnosed Glioblastoma
Estimated Study Start Date : April 30, 2020
Estimated Primary Completion Date : April 12, 2023
Estimated Study Completion Date : November 20, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Adjuvant Treatment
CC-90010-with standard dose TMZ
Drug: CC-90010
CC-90010 (eg.dose levels 15mg, 30mg, 45 mg) will be given once daily by mouth 4 days on/24 days off every 28-day cycle for 6 cycles. If subjects complete this period with no evidence of disease progression per RANO criteria, subject might receive CC-90010 as monotherapy at RP2D of 45 mg given 4 days on/24 days off in each 28-day cycle, until stopping criteria are met.

Drug: Temozolomide
Temozolomide

Drug: CC-90010
CC-90010 (e.g., 15 mg, 30 mg and 45 mg) will be given orally once daily (4 days on/24 days off) in combination with TMZ+RT for 42 days, to evaluate the initial toxicity of the combination. Following completion of 42 days of Concomitant Therapy, subjects who are fit to continue treatment will have a 4-week break before starting adjuvant therapy with CC-90010 in combination with TMZ.

Drug: Temozolomide
TMZ will be given orally at the standard dose of 75 mg/m2 per day for 7 days per week from the first day of radiotherapy until the last day of radiotherapy for 42 days. Following completion of 42 days of Concomitant Therapy, subjects who are fit to continue treatment will have a 4-week break before starting adjuvant therapy.

Experimental: Concomitant treatment.
CC-90010 combined with standard dose TMZ and RT
Drug: CC-90010
CC-90010 (eg.dose levels 15mg, 30mg, 45 mg) will be given once daily by mouth 4 days on/24 days off every 28-day cycle for 6 cycles. If subjects complete this period with no evidence of disease progression per RANO criteria, subject might receive CC-90010 as monotherapy at RP2D of 45 mg given 4 days on/24 days off in each 28-day cycle, until stopping criteria are met.

Drug: Temozolomide
Temozolomide

Drug: CC-90010
CC-90010 (e.g., 15 mg, 30 mg and 45 mg) will be given orally once daily (4 days on/24 days off) in combination with TMZ+RT for 42 days, to evaluate the initial toxicity of the combination. Following completion of 42 days of Concomitant Therapy, subjects who are fit to continue treatment will have a 4-week break before starting adjuvant therapy with CC-90010 in combination with TMZ.

Drug: Temozolomide
TMZ will be given orally at the standard dose of 75 mg/m2 per day for 7 days per week from the first day of radiotherapy until the last day of radiotherapy for 42 days. Following completion of 42 days of Concomitant Therapy, subjects who are fit to continue treatment will have a 4-week break before starting adjuvant therapy.




Primary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: Up to 5 years ]
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.

  2. Maximum Tolerated Dose (MTD) of CC-90010 [ Time Frame: Up to 12-14 months ]
    Is the highest dose that causes DLTs in not more than 33% of the subjects treated with CC-90010 in the first cycle with at least 6 evaluable subjects treated at this dose.

  3. Recommended Phase 2 Dose (RP2D) of CC-90010 [ Time Frame: Up to 12-14 months ]
    RP2D is usually the highest dose with acceptable toxicity, it might be the MTD or one dose level below.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Up to 5 years ]
    It is defined as the time from the first dose of CC-90010 to the first occurrence of disease progression or death from any cause.

  2. Overall survival (OS) [ Time Frame: Up to 5 years ]
    It is measured as the time from the first dose of CC-90010 to death due to any cause and will be analyzed in a manner similar to that described for PFS.

  3. Time to Progression [ Time Frame: Up to 5 years ]
    It is defined as the time from the first dose of CC-90010 until disease progression

  4. Response by Response Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: Up to 5 years ]
    Response should be assessed per RANO criteria. During Adjuvant Therapy, subjects will be evaluated for preliminary anti-tumor activity with MRI scan at the end of Cycle 2 and every even numbered Cycle (±7 days). During Concomitant Therapy, subjects will be initially evaluated for anti-tumor activity on Day 70 (-7 days) or at the end of week 10 (-1 week), following completion of the combination treatment of CC-90010+TMZ+RT. The Week 10 MRI scan must be interpreted before the subject can start Adjuvant Therapy

  5. Pharmacokinetics- Cmax [ Time Frame: Up to 2 years ]
    Maximum observed plasma concentration

  6. Pharmacokinetics- AUC [ Time Frame: Up to 2 years ]
    Area under the plasma concentration time-curve

  7. Pharmacokinetics- Tmax [ Time Frame: Up to 2 years ]
    Time to maximum plasma concentration

  8. Pharmacokinetics- t1/2 [ Time Frame: Up to 2 years ]
    Terminal half-life

  9. Pharmacokinetics - CL/F [ Time Frame: Up to 2 years ]
    Apparent clearance

  10. Pharmacokinetics - VzF [ Time Frame: Up to 2 years ]
    Apparent volume of distribution



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study criteria:

  1. Males and females of ≥ 18 years of age at the time of signing the informed consent form (ICF).
  2. Newly diagnosed, histologically confirmed WHO Grade IV Glioblastoma and must have undergone complete or partial tumor resection.
  3. Toxicities resulting from surgery must have resolved to NCI CTCAE (v5.0) Grade ≤ 1 prior to starting CC-90010 treatment (with the exception of Grade 2 alopecia).
  4. For Concomitant Therapy: Prior tumor resection up to 8 weeks prior to the first dose of CC-90010.
  5. For Adjuvant Therapy: Subject must have recently completed standard or a hypofractionated course of radiotherapy with TMZ chemotherapy, and then have an MRI documenting stable disease prior to the first dose of CC 90010.
  6. For Adjuvant Therapy:

    1. All AEs resulting from prior RT+TMZ chemotherapy must have resolved to NCI CTCAE (v5.0) Grade 1 (except for laboratory parameters outlined below).
    2. Subject must have not experienced significant toxicity to prior RT+TMZ (i.e., Grade 4 hematological toxicity)
    3. Subject must have received at least 80% of the planned standard doses of RT and/or TMZ administered throughout the 42 day concomitant period (up to 49 days).
  7. Subject with archival tumor tissue suitable for molecular genetic testing must give permission to access and test the tissue.
  8. Life expectancy of at least 3 months.
  9. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1.
  10. Subject must have the following laboratory values at screening:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support for 7 days (14 days if subject received pegfilgrastim).
    2. Hemoglobin (Hgb) ≥10 g/dL
    3. Platelet count (plt) ≥150 x 109/L
    4. Serum potassium concentration within normal range, or correctable with supplements
    5. Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamate pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 3.0 x Upper Limit of Normal (ULN).
    6. Serum total bilirubin ≤ 1.5 x ULN.
    7. Serum creatinine ≤ 1.5 x ULN or measured glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m2 using an exogenous filtration marker such as iohexol, inulin, 51Cr EDTA or 1125 iothalamate, or creatinine clearance of ≥ 50 mL/min using Cockroft-Gault equation.
    8. Serum albumin > 3.5 g/dL
    9. PT (or INR) and APTT within normal range
  11. Females of childbearing potential (FCBP) and men with partners of child bearing potential must agree to take contraceptive measures for duration of treatment and for at least 46 days after last dose of CC-90010 for females and for 106 days after last dose of CC-90010 for males, and for 180 days after last dose of Temozolomide for both males and females
  12. Males must agree to refrain from donating semen while on study drug and for 106 days after discontinuation of CC-90010 or 180 days after the last dose of TMZ, whichever is longer.
  13. Females must agree to refrain from donating ova while on study treatment and for 46 days after the last dose of CC-90010 or 180 days after the last dose of TMZ, whichever is longer.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

  1. Prior chemotherapy or other anti-tumor treatment for GBM (either approved or investigational) except for surgery and for the Adjuvant Therapy cohort, mandatory concomitant TMZ+RT.
  2. Subject has persistent diarrhea due to a malabsorptive syndrome (such as celiac sprue or inflammatory bowel disease) NCI CTCAE Grade ≥ 2, despite medical management, or any other significant GI disorder that could affect the absorption of CC-90010.
  3. Subject with symptomatic or uncontrolled ulcers (gastric or duodenal), particularly those with a history of and/or risk of perforation and GI tract hemorrhages.
  4. Evidence of recent, symptomatic CNS hemorrhage on baseline MRI or CT scan.
  5. Subject who requires increasing doses of corticosteroids to treat symptomatic cerebral edema within 14 days prior to the first dose of CC-90010.
  6. Known symptomatic acute or chronic pancreatitis.
  7. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

    • LVEF < 45% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
    • Complete left bundle branch or bifascicular block.
    • Congenital long QT syndrome.
    • Persistent or clinically meaningful ventricular arrhythmias or atrial fibrillation.
    • QTcF ≥ 480 milliseconds (msec) on Screening ECG (mean of triplicate recordings); a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 msec (CTCAE Grade ≥ 2), using Fridericia's QT correction formula.
    • A history of additional risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
    • The use of concomitant medications that prolong the QT/QTc interval.
    • Unstable angina or myocardial infarction ≤ 6 months prior to starting CC-90010.
    • Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension (blood pressure ≥ 160/95 mm Hg).
  8. Pregnant or nursing females.
  9. Known HIV infection.
  10. Known chronic active hepatitis B or C virus (HBV, HCV) infection.

    • Subjects who are seropositive due to HBV vaccination are eligible.
    • Subjects who have no active viral infection and are under adequate prophylactics against HBV re-activation are eligible.
  11. Subject with a requirement for ongoing treatment with therapeutic dosing of anticoagulants (e.g., warfarin, low molecular weight heparin, Factor Xa inhibitors, thrombin antagonists), or for ongoing prophylactic anticoagulation. Low dose low molecular weight heparin for catheter maintenance is allowed.
  12. History of concurrent second cancers requiring active and ongoing systemic treatment, except non-melanoma skin cancer, completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score ≤ 6 and PSA < 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance. Other cancers for which the subject has completed potentially curative treatment more than 3 years prior to study entry are allowed.
  13. Evidence of history of bleeding diathesis. Any hemorrhage/bleeding event > CTCAE Grade 2 or haemoptysis > 1 teaspoon within 4 weeks prior to the first dose of CC-90010.
  14. Subject with known prior episodes of non-arteritic anterior ischemic optic neuropathy (NAION) should be excluded from the study. CC-90010 should be used with caution in subjects with retinitis pigmentosa.
  15. Subject has any significant medical condition (e.g., active or uncontrolled infection, hepatic or renal disease), laboratory abnormality, or psychiatric illness that would prevent the subject from participating (or compromise compliance) in the study or would place the subject at unacceptable risk if he/she were to participate in the study.
  16. Subject has any condition that confounds the ability to interpret data from the study.
  17. Subject with poor bone marrow reserve as assessed by Investigator such as in conditions requiring regular hematopoietic support (blood or platelet transfusions, erythropoietin, granulocyte colony stimulating factor [GCSF] or other hematopoietic growth factors).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04324840


Contacts
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Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
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Italy
Ospedale San Raffaele
Milano, Italy, 20132
Istituto Clinico Humanitas
Milan, Italy, 20089
Policlinico San Matteo Universita Di Pavia
Pavia, Italy, 27100
Azienda Ospedaliera Universitaria Integrata Verona
Verona, Italy, 37126
Netherlands
Erasmus Universitair Medisch Centrum
Rotterdam, Netherlands, 3015 GD
University Medical Center Utrecht
Utrecht, Netherlands, 3584 CX
Spain
Hospital Val d´Hebron
Barcelona, Spain, 08035
Hospital Universitario Fundacion Jimenez Diaz
Madrid, Spain, 28040
Hospital Doce de Octubre
Madrid, Spain, 28041
Sponsors and Collaborators
Celgene
Investigators
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Study Director: Zariana Nikolova, MD, PhD Celgene
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT04324840    
Other Study ID Numbers: CC-90010-GBM-002
U1111-1248-0496 ( Other Identifier: WHO )
2019-004122-25 ( EudraCT Number )
First Posted: March 27, 2020    Key Record Dates
Last Update Posted: April 30, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: See Plan Description
Access Criteria: See Plan Description
URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene:
CC-90010
Temozolomide
Glioblastoma
NEWLY DIAGNOSED
Radiation therapy
Safety
Tolerability
MTD and RP2D
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents