Trial Title:
Bortezomib and Pembrolizumab With or Without Pelareorep for the Treatment of Relapsed or Refractory Multiple Myeloma, AMBUSH Trial
NCT ID:
NCT05514990
Condition:
Recurrent Plasma Cell Myeloma
Refractory Plasma Cell Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Dexamethasone
Dexamethasone acetate
Pembrolizumab
Bortezomib
Ichthammol
BB 1101
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Bortezomib
Description:
Given SC or IV
Arm group label:
Cohort I (standard therapy)
Arm group label:
Cohort II (standard therapy, pelareorep)
Other name:
[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
Other name:
LDP 341
Other name:
MLN341
Other name:
PS-341
Other name:
PS341
Other name:
Velcade
Intervention type:
Drug
Intervention name:
Dexamethasone
Description:
Given PO, IV, or IM
Arm group label:
Cohort I (standard therapy)
Arm group label:
Cohort II (standard therapy, pelareorep)
Other name:
Aacidexam
Other name:
Adexone
Other name:
Aknichthol Dexa
Other name:
Alba-Dex
Other name:
Alin
Other name:
Alin Depot
Other name:
Alin Oftalmico
Other name:
Amplidermis
Other name:
Anemul mono
Other name:
Auricularum
Other name:
Auxiloson
Other name:
Baycadron
Other name:
Baycuten
Other name:
Baycuten N
Other name:
Cortidexason
Other name:
Cortisumman
Other name:
Decacort
Other name:
Decadrol
Other name:
Decadron
Other name:
Decadron DP
Other name:
Decalix
Other name:
Decameth
Other name:
Decasone R.p.
Other name:
Dectancyl
Other name:
Dekacort
Other name:
Deltafluorene
Other name:
Deronil
Other name:
Desamethasone
Other name:
Desameton
Other name:
Dexa-Mamallet
Other name:
Dexa-Rhinosan
Other name:
Dexa-Scheroson
Other name:
Dexa-sine
Other name:
Dexacortal
Other name:
Dexacortin
Other name:
Dexafarma
Other name:
Dexafluorene
Other name:
Dexalocal
Other name:
Dexamecortin
Other name:
Dexameth
Other name:
Dexamethasone Intensol
Other name:
Dexamethasonum
Other name:
Dexamonozon
Other name:
Dexapos
Other name:
Dexinoral
Other name:
Dexone
Other name:
Dinormon
Other name:
Dxevo
Other name:
Fluorodelta
Other name:
Fortecortin
Other name:
Gammacorten
Other name:
Hemady
Other name:
Hexadecadrol
Other name:
Hexadrol
Other name:
Lokalison-F
Other name:
Loverine
Other name:
Methylfluorprednisolone
Other name:
Millicorten
Other name:
Mymethasone
Other name:
Orgadrone
Other name:
Spersadex
Other name:
TaperDex
Other name:
Visumetazone
Other name:
ZoDex
Intervention type:
Biological
Intervention name:
Pelareorep
Description:
Given IV
Arm group label:
Cohort II (standard therapy, pelareorep)
Other name:
PO BB0209
Other name:
PO-BB0209
Other name:
Reolysin
Other name:
Reovirus Serotype 3
Other name:
Wild-type Reovirus
Intervention type:
Biological
Intervention name:
Pembrolizumab
Description:
Given IV
Arm group label:
Cohort I (standard therapy)
Arm group label:
Cohort II (standard therapy, pelareorep)
Other name:
Keytruda
Other name:
Lambrolizumab
Other name:
MK-3475
Other name:
SCH 900475
Summary:
This phase I/II trial studies the safety of the combination of bortezomib, dexamethasone,
and pembrolizumab with or without pelareorep in treating patients with multiple myeloma
that has come back (relapsed) or does not response to treatment (refractory).
Chemotherapy drugs, such as bortezomib and dexamethasone, work in different ways to stop
the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as
pembrolizumab, may help the body's immune system attack the cancer, and may interfere
with the ability of tumor cells to grow and spread. A virus modified in the laboratory,
such as pelareorep, may be able to kill cancer cells without damaging normal cells.
Giving the combination of bortezomib, dexamethasone, and pembrolizumab with pelareorep
may work better in treating patient with multiple myeloma.
Detailed description:
PRIMARY OBJECTIVES:
I. To establish the safety of bortezomib-dexamethasone (BOR-D) and pembrolizumab (cohort
1) and its combination with pelareorep (PELA) (cohorts 2). (Phase 1B) II. To determine
the recommended phase 2 dose (RP2D) for PELA in combination with BOR-D and pembrolizumab
in patients with relapsed or refractory multiple myeloma (RRMM; cohorts 2). (Phase 1B)
III. To estimate the efficacy of the combination of PELA, BOR -D and pembrolizumab in
patients with RRMM. (Phase 2)
SECONDARY OBJECTIVES:
I. To evaluate the efficacy PELA in combination with BOR-D and pembrolizumab (cohorts 2)
in patients with RRMM. (Phase 1B) II. To characterize the safety and tolerability of the
combination, including acute and chronic toxicities. (Phase 2)
EXPLORATORY OBJECTIVES:
I. To compare changes in the tumor microenvironment (TME) and immune responses in
patients treated with BOR-D and pembrolizumab (cohort 1) to patients treated with PELA,
BOR-D, and pembrolizumab (cohort 2). (Phase 1B) II. To evaluate changes in the TME and
immune responses in patients treated with the combination of PELA, BOR-D and
pembrolizumab. (Phase 2)
OUTLINE: This is a phase IB dose escalation study followed by a phase II study. Patients
are assigned to 1 of 2 cohorts.
COHORT I: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) and
dexamethasone orally (PO), IV, or intramuscularly (IM) on days 1, 8, and 15 of each
cycle. Patients also receive pembrolizumab IV over 30 minutes on day 9 of each cycle.
Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression
or unacceptable toxicity.
COHORT II: Patients receive bortezomib SC or IV and dexamethasone either PO, IV, or IM on
days 1, 8, and 15 of each cycle. Patients also receive pelareorep IV over 60 minutes on
days 1, 2, 8, 9, 15, and 16 and pembrolizumab IV over 30 minutes on day 9 of each cycle.
Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression
or unacceptable toxicity.
After completion of study, patients are followed-up every 12 weeks or every 6 months
depending on status of disease.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Relapsed or refractory multiple myeloma (MM) after at least 3 previous lines of
therapy. Previous treatment must have included a proteasome inhibitor (bortezomib,
ixazomib or carfilzomib), an immunomodulatory agent (thalidomide, lenalidomide or
pomalidomide) and an anti cd38 monoclonal antibody.
- Histologically confirmed diagnosis of MM with measurable disease, as defined by the
presence of monoclonal immunoglobulin protein in serum electrophoreses of at least
0.5 g/dL for immunoglobulin G (IgG) or 0.25 g/dL for IgA, or measurable light chain
in serum (100 mg/L) or urinary excretion of at least 200 mg monoclonal light chain
per 24 hours.
- No continuing acute toxic effects (except alopecia) of any prior chemotherapy,
radiotherapy or surgical procedures. All such effects must have resolved to Common
Terminology Criteria for Adverse Events (CTCAE), version 5.0 grade =< 1. Surgery
(except minor procedures such as biopsies, intravenous [IV]-line placement, etc.)
must have occurred at least 28 days prior to study enrollment.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
- Male or female >= 18 years of age at the time of signing the informed consent form
(ICF).
- Life expectancy of at least 3 months.
- Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of relapse, refractory
multiple myeloma will be enrolled in this study.
- A male participant must agree to use a contraception during the treatment period and
for at least 7 months after the last dose of study treatment and refrain from
donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during
the treatment period and for at least 7 months after the last dose of study
treatment.
- The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial, indicating that the patient is aware of the
neoplastic nature of their disease and have been informed of the procedures of the
protocol, the experimental nature of the therapy, possible alternative therapies,
potential benefits, side effects, risks, and discomforts.
- Be willing and able to comply with scheduled visits, the treatment plan, and
laboratory tests.
- Absolute neutrophil count (ANC) >= 1000/uL (collected within 10 days prior to the
start of study intervention).
- Platelets >= 50,000/uL (collected within 10 days prior to the start of study
intervention).
- Hemoglobin >= 8.0 g/dL or >= 5.0 mmol/L.
- Creatinine =< 1.5 x upper limit of normal (ULN) or measured or calculated creatinine
clearance (glomerular filtration rate [GFR] can also be used in place of creatinine
or creatinine clearance ([CrCl]) >= 30 mL/min for participant with creatinine levels
> 1.5 x institutional ULN (collected within 10 days prior to the start of study
intervention).
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 x ULN (collected within 10 days prior to the start of study
intervention).
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase) [SGOT])
and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase) [SGPT]) =<
2.5 x ULN (=< 5 x ULN for participants with liver metastases) (collected within 10
days prior to the start of study intervention).
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
participant is receiving anticoagulant therapy as long as PT or activated partial
thromboplastin time (aPTT) is within therapeutic range of intended use of
anticoagulants (collected within 10 days prior to the start of study intervention).
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants (collected within 10 days prior to the start of study
intervention).
- Proteinuria normal or grade 1 based on 24-urine collection test. Patients with
proteinuria >= grade 2 due to light chains in the urine may be eligible based on
review of screening urine electrophoresis results.
- Thyroid-stimulating hormone (TSH), thyroxine (T4) and adrenocorticotropic hormone
(ACTH) within normal limits. Patients under treatment for hormonal abnormality(s)
will be individually assessed for inclusion based on their history and current
status.
- Criteria for known Hepatitis B and C positive subjects. Hepatitis B and C screening
tests are not required unless:
- Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- As mandated by local health authority.
- Hepatitis B positive subjects:
- Participants who are hepatitis B surface antigen (HBsAg) positive are eligible
if they have received HBV antiviral therapy for at least 4 weeks and have
undetectable HBV viral load prior to randomization.
- Participants should remain on anti-viral therapy throughout study intervention
and follow local guidelines for HBV anti-viral therapy post completion of study
intervention.
- Participants with history of HCV infection are eligible if HCV viral load is
undetectable at screening.
- Participants must have completed curative anti-viral therapy at least 4 weeks
prior to randomization.
Exclusion Criteria:
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
- Note: in the event that 72 hours have elapsed between the screening pregnancy
test and the first dose of study treatment, another pregnancy test (urine or
serum) must be performed and must be negative in order for subject to start
receiving study medication.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,
CTLA-4, OX-40, CD137).
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to allocation.
- Note: Participants must have recovered from all AEs due to previous therapies
to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be
eligible. Participants with endocrine -related AEs grade =< 2 requiring
treatment or hormone replacement may be eligible.
- Note: If the participant had major surgery, the participant must have recovered
adequately from the procedure and/or any complications from the surgery prior
to starting study intervention.
- Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central
nervous system (CNS) disease. Palliative radiotherapy is allowed while on study
treatment for treatment of symptomatic lesions.
- Has received a live vaccine or live-attenuated vaccine within 30 days before the
first dose of study intervention. Examples of live vaccines include, but are not
limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox),
yellow fever, rabies, bacillus calmette-guerin (BCG), and typhoid vaccine. Seasonal
influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated
vaccines and are not allowed.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose
of study intervention.
- Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Known additional malignancy that is progressing or has required active treatment
within the past 5 years.
- Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, superficial bladder cancer, prostate intraepithelial
neoplasm, carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) or
other noninvasive or indolent hat have undergone potentially curative therapy
are not excluded.
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening),
clinically stable and without requirement of steroid treatment for at least 14 days
prior to first dose of study intervention.
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its
excipients.
- Has active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV) infection.
- Note: No HIV testing is required unless mandated by local health authority.
- Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV
deoxyribonucleic acid [DNA]) and hepatitis C virus (defined as anti-HCV Ab positive
and detectable HCV ribonucleic acid [RNA]) infection.
- Note: Hepatitis B and C screening tests are not required unless:
- Known history of HBV and HCV infection.
- As mandated by local health authority.
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant to participate, in the
opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
- Has had an allogenic tissue/solid organ transplant.
- History or prior allogenic stem cell transplant.
- Receipt of concurrent immunosuppressive therapy.
- Clinically significant cardiac disease (New York Heart Association, Class III or IV)
including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial
infarction 1 year prior to study entry, or a known history of grade 2 or higher
compromised left ventricular ejection fraction.
- Dementia or altered mental status that would prohibit informed consent.
- Has a history of or current evidence of any other severe, acute or chronic medical
or psychiatric condition, therapy or laboratory abnormality that may increase the
risk associated with study participation or study drug administration or may
interfere with the interpretation of study results and, in the judgment of the
principal investigator, would make the patient inappropriate for this study.
- History of allergic (anaphylactic) sensitivity to bortezomib, boron or mannitol.
- Grade 2 or greater neuropathy at the time of screening.
- Has a known history of active TB (Bacillus tuberculosis).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Los Angeles County-USC Medical Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Last name:
Kevin R. Kelly
Phone:
323-865-3000
Email:
kevin.kelly@med.usc.edu
Investigator:
Last name:
Kevin R. Kelly
Email:
Principal Investigator
Facility:
Name:
USC / Norris Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Last name:
Kevin R. Kelly
Phone:
323-865-3000
Email:
kevin.kelly@med.usc.edu
Investigator:
Last name:
Kevin R. Kelly
Email:
Principal Investigator
Start date:
October 7, 2022
Completion date:
October 7, 2026
Lead sponsor:
Agency:
University of Southern California
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
University of Southern California
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05514990