Phase II, Multicenter Study to Assess Safety and Efficacy of Combination of Sargramostim with D-VCd Therapy (Daratumumab, Cyclophosphamide, Bortezomib, Dexamethasone) in Untreated Patients with Light Chain Amyloidosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Warsaw

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Jul 2023 → ongoing

Decision date (initial)

2024-12-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518658-18-00

EudraCT number

2021-005769-42

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy based on the percentage of patients with a complete hematologic response (CHR)
To assess the safety based on the percentage of patients with serious adverse events (SAEs)

Secondary objectives 9

1. To evaluate overall hematologic response rate (OHRR)
2. To evaluate organ response rate (OrRR)
3. To evaluate minimal residual disease (MRD)
4. To evaluate hematologic progression free survival (PFS)
5. To evaluate overall survival (OS)
6. To evaluate time to response
7. To evaluate time to organ progression
8. To assess the safety and tolerability of sargramostim in combination with D-VCd
9. To assess patient-reported outcomes (PRO)

Conditions and MedDRA coding

Light chain amyloidosis (AL amyloidosis) is an incurable plasma cell neoplasm and the most common among a heterogeneous group of over 30 rare and ultra-rare diseases known as amyloidoses. In AL amyloidosis the deposition of amyloid fibrils resulting from misfolded immunoglobulin light chains leads to end-stage failure of the affected organs, most often of the heart or kidneys. Current therapy of AL amyloidosis is based on the destruction of clonal plasma cells with chemotherapy or immunotherapy, which leads to the inhibition of the production of immunoglobulin light chains, which are the precursors of amyloid. Effective inhibition of amyloid production enables slow resorption of already formed deposits, which results in organ responses in some patients. In vitro and in vivo studies showed amyloid deposits removal via phagocytosis by macrophages and neutrophils.So far, no therapies have been approved that would directly affect the amyloid deposits, however, clinical trials with opsonizing antibodies are ongoing,he mechanism of which is binding and neutralization of amyloid deposits in the process of phagocytosis. In 2021, based on the results of the ANDROMEDA phase III clinical trial, the most effective therapy for AL amyloidosis was registered so far: the D-VCD regimen combining anti-CD38 monoclonal antibody, daratumumab, with standard chemotherapy bortezomib, cyclophosphamide and dexamethasone. The recombinant granulocyte macrophage colony stimulating factor (GM-CSF) sargramostim will be used in this study with the D-VCD regimen. Currently, the indication for its use in the USA includes mobilization of progenitor cells and support for the reconstruction of white blood cells after autologous bone marrow transplantation, induction treatment of acute myeloid leukemia and myelosuppressive radiation.In patients with rheumatoid arthritis, a relationship between high levels of GM-CSF in the synovial fluid and a lower risk of developing Alzheimer's disease, which is associated with the accumulation of amyloid beta deposits in the brain, has been observed. In studies in a transgenic mouse model, it was shown that injections of GM-CSF led to a rapid reduction in the amount of beta amyloid in the brain and to neurological improvement. In a recent clinical trial in patients with Alzheimer's disease, a 3-week treatment with sargramostim resulted in improved cognitive function, decrease plasma markers of neurodegeneration and increase of amyloid beta (decreased in AD) compared to placebo. We assume that activation of tissue phagocytes thanks to the use of sargramostim will result in more effective phagocytosis of amyloid deposits, which, together with the active destruction of clonal plasma cells by D-VCd immunochemotherapy, may lead to an increase in the frequency of organ responses.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 18 years of age or older.
2. Histopathological diagnosis of AL amyloidosis based on detection by polarizing light microscopy of green bi-refringent material in Congo red-stained tissue specimens (in an organ other than bone marrow) and typing of AL amyloid in a tissue specimen by IHC or immune electron microscopy or mass spectrometry.
3. Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:a) serum M-protein ≥0.5 g/dL by routine protein serum protein electrophoresis and immunofixation (IFE), b) serum free light chain ≥50 mg/L with an abnormal kappa: lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥50 mg/L. Note: Measurable disease by urine Bence-Jones proteinuria is not sufficient for study enrollment.
4. One or more organs impacted by AL amyloidosis according to consensus guidelines.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
6. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:a. Absolute neutrophil count (ANC) ≥1.0 × 109 /L b. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before enrollment c. Platelet count ≥50 × 109 /L; Platelet transfusions are acceptable without restriction during the Screening Period d. Alanine aminotransferase level (ALT) ≤2.5 times the upper limit of normal (ULN) e. Aspartate aminotransferase (AST) ≤2.5 times the ULN f. Total bilirubin level ≤1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin ≤2 × ULN g. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
7. A woman of childbearing potential must have a negative serum or urine pregnancy test (serum preferred) result at screening and must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to C1D1 and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8. During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
10. Each subject, or legally acceptable representative, must sign an informed consent form (ICF) indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.

Exclusion criteria 19

1. Prior therapy for AL amyloidosis or multiple myeloma, except for 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure.
2. Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, infiltration with ≥60% clonal plasma cells in the bone marrow, or hypercalcemia (serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
3. Evidence of significant cardiovascular conditions as specified below:a. NT-ProBNP >8500 pg/ml (ng/L); b. New York Heart Association (NYHA) classification IIIB or IV heart failure; c. Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (e.g. prior myocardial infarction with documented history of cardiac enzyme elevation and ECG changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy; d. Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months; e. For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to enrollment;f. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (subjects who do have a pacemaker/ICD are allowed in the study); g. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec. Subjects who have a pacemaker may be included regardless of calculated QTc interval; h. Supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of 20 mmHg despite medical management (e.g., midodrine, fludrocortisone) in the absence of volume depletion.
4. Planned stem cell mobilization, collection, and stem cell transplant during the first 6 cycles of protocol therapy. Note: stem cell mobilization, collection and transplantation are allowed after study treatment completion.
5. History of malignancy (other than AL amyloidosis) within 3 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other lesion that in the opinion of the investigator, with concurrence with the sponsor, is considered cured and/or with minimal risk of recurrence or progression within 3 years).
6. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required only for subjects suspected of having COPD and subjects must be excluded if FEV1 < 50% of predicted normal.
7. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
8. Known to be seropositive for human immunodeficiency virus (HIV).
9. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
10. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
11. Grade 2 sensory or Grade 1 painful peripheral neuropathy.
12. Known hypersensitivity or contraindication to any of the components of study drugs including sargramostim, daratumumab, bortezomib, boron, mannitol, or cyclophosphamide, dexamethasone, or any of its metabolites. Patients with known hypersensitivity to GM-CSF and yeast-derived products or any component of the product. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products.
13. Concurrent medical condition or disease (e.g. active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
14. Any form of non-AL amyloidosis, including wild type or mutated ATTR amyloidosis.
15. Known or suspected of not being able to comply with the study protocol (e.g. because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g. compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
16. Woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 3 months following discontinuation of daratumumab, whichever is longer
17. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1 Day 1.
18. Major surgery within 2 weeks before Cycle 1 Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study treatment administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.
19. Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the first dose of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Complete hematologic response rate (CHRR) (from the first response evaluation to the end of combination treatment (EOCT) assessment)
2. Serious adverse events rate (measured from the date of informed consent form is signed to the EOCT assessment)

Secondary endpoints 4

1. Overall hematologic response rate (OHRR) (from the first response evaluation to the EOCT assessment)
2. Organ response rate (OrRR) for heart, kidney, liver (from the first response evaluation to the last assessment)
3. Minimal residual disease (MRD) status (measured at the time CHR is assessed)
4. Hematologic progression free survival (PFS) (measured from C1D1 to the date of first documentation of hematologic progression, or death due to any cause, whichever occurs first)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Warsaw

Sponsor organisation

Medical University Of Warsaw

Address

Ul. Zwirki I Wigury 61

City

Warsaw

Postcode

02-091

Country

Poland

Scientific contact point

Organisation

Medical University Of Warsaw

Contact name

Krzysztof

Public contact point

Organisation

Medical University Of Warsaw

Contact name

Krzysztof

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications