Study of CC-122 to Evaluate the Safety, Tolerability, and Effectiveness for Patients With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase 1a/1b, Multi-center, Open-label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Pleiotropic Pathway Modifier CC-122 Administered Orally to Subjects With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01421524
• Other study ID #: CC-122-ST-001
• Secondary ID: U1111-1203-5132
• Status: Completed
• Phase: Phase 1
• Start date: September 12, 2011
• Est. completion date: November 21, 2023

Study information

• Verified date: November 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main purpose of this first in human study with CC-122 is to assess the safety and action of a new class of experimental drug (Pleiotropic Pathway Modulator) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dosing level and regimen for later-stage clinical trials.

Description:

This trial is enrolling additional Multiple Myeloma (MM) subjects in a separate cohort defined as MM-2 to evaluate tolerability, safety and preliminary efficacy of CC-122 formulated capsule alone or in combination with DEX on intermittent dosing schedule (5 of 7 days of the week) in Pomalidomide-naïve subjects. Preliminary efficacy data in Multiple Myeloma subjects, warrants further exploration of CC-122 in MM on intermittent schedules to assess if dose intensity and tolerability can be improved. Initially, patients will be treated with oral CC-122 for one month. During this time, various tests (involving blood and urine collections, ECGs, etc) will be performed. Those whose tumors stabilize or regress may continue receiving treatment for as long as they benefit from CC-122. Different dose levels of CC-122 will be tested in a dose-rising study design.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 271
• Est. completion date: November 21, 2023
• Est. primary completion date: November 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.

2. Men and women, 18 years or older, with histologically or cytologically-confirmed, advanced solid tumors, Non-Hodgkin Lymphona (NHL), Multiple Myloma (MM), or advanced unresectable solid tumors limited to the tumor types below.

1. Subjects who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no standard anticancer therapy exists. Must have disease that is objectively measurable

2. Measurable disease criteria:

• Subjects with Glioblastoma multiforme (GBM) do not have to have objectively measurable disease at entry.

• For MM, Diffuse large B-cell lymphoma (DLBCL): Subjects must have disease that is objectively measurable, measurable levels of myeloma paraprotein in serum (> 0.5 g/dL) or urine (> 0.2 g excreted in a 24-hour collection sample) for MM and measurable disease by Internatonal Working Group (IWG) for NHL (with at least one measurable lesion's longest diameter = 2cm).

• For Primary Central Nervous System (CNS) Lymphoma (PCNSL): Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary CNS Lymphoma, Cerebrospinal Fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma).

3. Tumor specific inclusion criteria:

• DLBCL-2 cohort:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of = 1.

• Histologically proven diffuse large B-cell non-Hodgkin's lymphoma

• Must have progressed following or have been unable to tolerate at least one prior anthracycline or alkylating agent containing regimen (with or without anti-CD20).

• Platelets = 60 x 109/L.

• For PCNSL cohort:

• ECOG Performance Status of = 2

• Recurrent/refractory CNS non-Hodgkin's lymphoma involving CNS (Brain, Cerebrospinal fluid (CSF) or intraocular compartments)

• Stable dose of glucocorticoids pre-therapy. If patients are receiving glucocorticoids, the dose should not increase during the 96 hours prior to initiation of therapy.

• ECOG Performance Status of = 2.

• For glioblastoma multiforme (GBM-2) cohort:

• ECOG Performance Status of = 2

• Primary GBM or gliosarcoma

• ECOG Performance Status of = 2.

• Has received prior treatment including radiation and chemotherapy, with radiation completed > 12 weeks prior to Day 1 (or = 4 weeks if the recurrence is outside of the prior radiation field).

• Progression of disease after last therapy demonstrated by RANO criteria

• No prior therapy with Avastin

• No prior or scheduled Gliadel® wafer implant unless area of assessment and planned resection is outside the region previously implanted.

• No prior interstitial brachytherapy or stereotactic radiosurgery unless area of assessment and planned resection is outside the region previously treated.

• No enzyme-inducing anti-epileptic drugs (EIAED) such as carbamazepine, phenytoin, phenobarbital, or primidone within 14 days before Day 1.

• Able to undergo repeated magnetic resonance imaging (magnetic resonance imaging (MRI), computed tomography (CT) scans).

• Availability of adequate Formalin-fixed, paraffin embedded (FFPE) archival tumor material.

• Platelets (plt) = 100 x 109/L.

• For Multiple Myeloma cohort

• ECOG Performance Status of = 1.

• Have a documented diagnosis of multiple myeloma and have relapsed and refractory disease.

• Measurable levels of myeloma paraprotein (M-protein) in serum (> 0.5 g/dL) or urine (> 0.2 g excreted in a 24-hour collection sample).

• Patients must have received at least 2 prior therapies.

• Patients must have relapsed after having achieved at least stable disease for at least one cycle of treatment to at least one prior regimen and then developed PD.

• Patients must also have documented evidence of PD during or within 60 days (measured from the end of the last cycle) of completing treatment with the last anti-myeloma drug regimen used just prior to study entry (refractory disease).

• Patients must have also undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteosome inhibitor (either in separate regimens or within the same regimen).

• Must be Pomalidomide naïve.

• Last dose of therapeutic glucocorticosteroids given greater than 14 days prior to start of study treatment.

• Platelets (plt) = 75 x 109/L in subjects in whom < 50% of bone marrow mononuclear cells are plasma cells or = 30 x 109/L in subjects in whom = 50% of bone marrow mononuclear cells are plasma cells.

4. At least 4 weeks from last dose of therapeutic glucocorticosteroids. Adrenal replacement doses of glucocorticosteroids (up to the equivalent of 10 mg daily prednisone) are allowed.

5. Biopsies (DLBLC, MM): Diagnostic archival FFPE (either in tumor blocks or sectioned/mounted specimens) may be submitted in lieu of a pre-study research biopsy if it has been obtained no more than 1 year prior to enrollment and only after discussion with the Celgene Medical Monitor

6. If not specified above as tumor specific parameter subjects must have the following laboratory and hematologic parameters as follows:

1. Absolute Neutrophil Count (ANC) = 1.5 x 109/L without growth factor support for 7 days (14 days if received pegfilgrastim).

2. Hemoglobin (Hgb) = 9 g/dL.

3. Platelets (Plt) =100 x 109/L.

4. Potassium within normal limits or correctable with supplements.

5. AST/SGOT and ALT/SGPT = 3 x upper limit of normal (ULN) or = 5.0 x ULN if liver tumor is present.

6. Serum creatinine = ULN (with value applied to Cockcroft-Gault equation) or 24 hour clearance = 50mL/min.

7. Negative serum pregnancy test in females of childbearing potential

Exclusion Criteria:

1. History of other carcinomas within the last 5 years except cured non-melanoma skin cancer, curatively treated in-situ cervical cancer, or localized prostate cancer with a current Prostate-specific antigen (PSA) of <1.0 mg/dL on 2 evaluations at least 3 months apart; the most recent evaluation must be no more than 4 weeks prior to Day 1 of the study drug, or other malignancies that were completely resected or treated Stage 1/2 lesions currently in complete remission.

2. Symptomatic central nervous system metastases (excluding Glioblastoma multiforrme (GBM) and Primary Central Nervous System Lymphoma (PCNSL). Subjects with brain metastases that have been previously treated and are stable for 6 weeks are allowed.

3. Known symptomatic acute or chronic pancreatitis.

4. Any peripheral neuropathy = National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 2.

5. Persistent diarrhea or malabsorption = NCI CTCAE grade 2, despite medical management.

6. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

1. left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiography (ECHO).

2. Complete left bundle branch, or bifasicular block.

3. Congenital long QT syndrome.

4. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.

5. QTcF > 460 msec on screening Electrocardiography (ECG) (mean of triplicate recordings).

6. Unstable angina pectoris or myocardial infarction = 3 months prior to starting CC-122.

7. Troponin-T value > 0.4 ng/ml or BNP >300 pg/mL.

° Subjects with baseline troponin-T >Upper Limit of Normal (ULN) or B-type Natriuretic Peptide (BNP) >100 pg/mL are eligible but must have cardiologist evaluation prior to enrollment in the trial for baseline assessment and optimization of cardioprotective therapy.

8. Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension (blood pressure = 160/95 mmHg).

7. Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection or renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol.

8. Prior systemic cancer-directed treatments or investigational modalities = 5 half lives or 4 weeks, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy.

9. Major surgery = 2 weeks prior to starting study drug or still recovering from post operative side effects.

10. Women who are pregnant or breast feeding. Adults of reproductive potential not employing two forms of birth control as per Pregnancy Prevention Risk Management Plan.

11. Known Human immunodeficiency virus (HIV) infection.

12. Known chronic hepatitis B or C virus (HBV/HCV) infection, unless comorbidity in subjects with Hepatocellular carcinoma (HCC).

13. Status post solid organ transplant.

14. Less than 100 days for subjects receiving autologous hematologic stem cell transplant (HSCT); or 6 months for subjects receiving allogenic HSCT or either transplant type, if otherwise not fully recovered from HSCT related toxicity.

15. For MM-2 cohort only: Hypersensitivity (eg, Rash Grade 3 or 4) to thalidomide, lenalidomide, or dexamethasone (MM-2b).

16. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

17. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

18. Any condition that confounds the ability to interpret data from the study.

Related Conditions & MeSH terms

• Glioblastoma
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Non-Hodgkin
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Pleiotropic Pathway Modifier
• Primary Central Nervous System Lymphoma

Intervention

Drug:
• CC-122
CC-122 dose in both arms will increase by 1 mg increments starting with 3 mg 5/7 days using the 3+3 design in dose escalation phase. A dose-level -1, with a starting dose of 2mg, may also be evaluated if the opening dose level is not tolerated. At all dose levels in MM-2b arm, DEX will be combined with CC-122 at a starting dose dependent on the subject's age: for subjects who are = 75 years of age, DEX 40 mg/day will be given on Days 1, 8, 15 and 22 of a 28-day cycle and for subjects who are > 75 years of age, DEX 20 mg/day will be given on Days 1, 8, 15 and 22 of a 28-day cycle. Approximately 33 subjects will be enrolled in the dose escalation phase (15 in each treatment arm). An additional intermittent schedule of 21/28 days may be evaluated per Safety Review Committee (SRC) decision. Following dose escalation, one or two arms will be expanded at or below the MTD in up to 28 subjects (14 subjects in each arm).
• CC-122
One or more intermittent schedules of CC-122 either given 5 continuous days out of 7 per week (5/7 days) or 21 continuous days out of 28 days per cycle (21/28 days). Following dose escalation, one or more of these intermittent schedules will be evaluated at a starting dose of 4 mg.
• CC-122
Dose escalation on a continous schedule will be evaluated at a starting dose of 4 mg. Specifically, dose levels with 1 mg increments (eg 4mg, 5mg, 6mg etc.) will be evaluated using a 3+3 design as detailed in Part A of the protocol .
• CC-122
Up to 10 subjects with relapsed or refractory PCNSL will be enrolled to a PCNSL cohort to evaluate intermittent schedules of CC-122 and to further explore preliminary signals of efficacy and biomarker hypotheses.

Locations

Country	Name	City	State
Belgium	Local Institution - 401	Bruxelles
Belgium	Local Institution - 400	Leuven
France	Local Institution - 202	Caen Cedex
France	Local Institution - 201	Marseille le Cedex
France	Local Institution - 205	Pierre Bénite
France	Local Institution - 203	Toulouse CEDEX 9
France	Local Institution - 200	Villejuif Cedex
Italy	Local Institution - 303	Bologna
Italy	Local Institution - 305	Bologna
Italy	Local Institution - 300	Milan
Italy	Local Institution - 302	Napoli, Campania
Italy	Local Institution - 304	Roma
Italy	Local Institution - 301	Rozzano (MI)
Spain	Local Institution - 103	Badalona (Barcelona)
Spain	Local Institution - 101	Barcelona
Spain	Local Institution - 105	Barcelona
Spain	Local Institution - 102	Madrid
Spain	Local Institution - 104	Madrid
Spain	Local Institution - 106	Pamplona
Spain	Local Institution - 108	Salamanca
Spain	Local Institution - 107	Sevilla
Spain	Local Institution - 100	Valencia
United States	University Of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	MUSC Rheumatology and Immunology Dept.	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Texas Oncology, PA - Dallas 75246	Dallas	Texas
United States	Henry Ford Medical Center - New Center One	Detroit	Michigan
United States	City of Hope Cancer Center	Duarte	California
United States	Greenville Hospital System	Greenville	South Carolina
United States	Comprehensive Cancer Centers Of Nevada	Las Vegas	Nevada
United States	UCLA Neuro-Oncology Program	Los Angeles	California
United States	Sarah Cannon Research Institute Drug Development Unit	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey University	New Brunswick	New Jersey
United States	Local Institution - 020	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	South Texas Accelerated Research Therapeutics (START)	San Antonio	Texas
United States	UCSF Helen Diller Medical Center at Parnassus Heights	San Francisco	California
United States	Swedish Medical Center Cancer Institute Research	Seattle	Washington
United States	Yakima Valley Memorial Hospital/ North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Spain, 

References & Publications (3)

Cubillos-Zapata C, Cordoba R, Avendano-Ortiz J, Arribas-Jimenez C, Hernandez-Jimenez E, Toledano V, Villaescusa T, Moreno V, Lopez-Collazo E. CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma. Oncoimmunology. 2016 Sep 16;5(12):e1231290. doi: 10.1080/2162402X.2016.1231290. eCollection 2016. — View Citation

Hagner P, et al. CC-122 Has Potent Anti-Lymphoma Activity through Destruction of the Aiolos and Ikaros Transcription Factors and Induction of Interferon Response Pathways. Presented at American Society of Hematology 2014, December 6-9, 2014, San Francisco, CA. Abstract No. 3035.

Rasco DW, Papadopoulos KP, Pourdehnad M, Gandhi AK, Hagner PR, Li Y, Wei X, Chopra R, Hege K, DiMartino J, Shih K. A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies. Clin Cancer Res. 2019 Jan 1;25(1):90-98. doi: 10.1158/1078-0432.CCR-18-1203. Epub 2018 Sep 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-Limiting Toxicity (DLT)	Dose-limiting toxicities (DLTs) will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE): A clinically relevant AE that is suspected to be related to CC-122 and starts = 30 days of first dose (Cycle 1) and = grade (Gr) 3 except for Alopecia, Gr3 rash of the acneiform or maculopapular type < 4 daysduration , Gr 3 diarrhea or vomiting lasting< 72 hours; Clinically relevant laboratory abnormality suspected to be related to CC-122 and that commences within 30 days of first dose and = Gr3.; Hematological toxicities as follows: Any febrile neutropenia (NP), Gr4 NP > 7 days, Gr 4 thrombocytopenia > 24 hours, Any Gr 3/4 thrombocytopenia with clinically significant bleeding.; Gr 4 liver function tests (LFTs) or Gr 3 ALT with = Gr2 bilirubin; Any AE suspected to be CC-122 related and necessitating dose reduction during Cycle 1.	Up to approximately Day 28
Primary	Pharmacokinetics- Cmax	Maximum observed concentration in plasma (Cmax)	Up to day 22
Primary	Pharmacokinetics- AUC	Area under the concentration-time curve	Up to day 22
Primary	Pharmacokinetics- tmax	Time to maximum concentration	Up to day 22
Primary	Pharmacokinetics- t1/2	Terminal half-life	Up to day 22
Primary	Pharmacokinetics- CL/F	Apparent total body clearance	Up to day 22
Primary	Pharmacokinetics- Vz/F	Apparent volume of distribution	Up to day 22
Primary	Non-tolerated dose (NTD)	Is defined as the dose level at which =2 out of 6 evaluable subjects in any dose cohort with DLT.	Up to day 28
Primary	Maximum Tolerated Dose (MTD)	Is defined as the last dose level below the NTD with =1 out of 6 evaluable subjects with DLT) during Cycle (C) 1.	Up to day 28
Secondary	Response Rate	The response rate of each tumor types based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), International Workshop Criteria (IWC) for Non-Hodgkin's Lymphoma (NHL), International Uniform Response Criteria for Multiple Myeloma (IURC), or Responses Assessment for Neuro-Oncology (RANO) working group for Glioblastama multiforme (GBM)	up to approximately 6 months
Secondary	Tissue concentration of CC-122	Tissue concentration of CC-122 in salvage resection specimens from subjects with GBM (CNS primary tumor) or in cerebrospinal fluid (CSF) from subjects undergoing lumbar puncture.	up to approximately 6 months
Secondary	6-month progression free survival (PFS) rate for GBM chort	The primary efficacy variable for GBM chohort is 6-month progression free survival (PFS).	Up to approximately 6 months

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