A Phase I/II Open-label, Multicentre, Dose Escalation and Expansion Study to Investigate the Safety, Tolerability, and Clinical Activity of Belantamab as Monotherapy and in Combination With Other Treatments in Participants With Multiple Myeloma

Study Identifier:
218670
CT.gov Identifier:
NCT05714839
EudraCT Identifier:
2022-501941-63
EU Trial (CTIS) Number:
2022-501941-63-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

The study consists of three parts:Part 1 The primary purpose of this part aims to evaluate the safety, tolerability, and clinical activity of escalating doses of single agent Unconjugated belantamab antibody in participants with refractory multiple myeloma (RRMM) who have received at least 3 prior therapies (4L+).

Part 2 The primary purpose of this part is to evaluate the safety, tolerability, and clinical activity of different dose ratios of belantamab mafodotin in combination with Unconjugated belantamab antibody (delivered as separate drugs) in participants with RRMM who have received at least 3 prior therapies (4L+).

Part 3: The Primary purpose of this part will evaluate the clinical activity of a selected dose of the unconjugated belantamab antibody, either alone or in combination with belantamab mafodotin alongside the standard of care (SoC) pomalidomide-dexamethasone backbone. The study will focus on patients with multiple myeloma who have undergone at least one prior line of therapy, including treatment with lenalidomide.

Primary Objective: To determine the safety and tolerability of IV administration of unconjugated BELANTAMAB antibody in participants with relapsed or refractory multiple myeloma (RRMM). Secondary Objectives: To explore the initial clinical activity of repeated doses of unconjugated BELANTAMAB in RRMM participants; to evaluate the pharmacokinetic characteristics of unconjugated BELANTAMAB antibody after single and repeated IV administrations in RRMM participants; and to assess the ADA of unconjugated BELANTAMAB antibody.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Multiple Myeloma
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Part 1: Dose escalation and expansion of the unconjugated belantamab antibody monotherapy
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Participants at the time of signing the Informed Consent Form (ICF) are at least 18 years old or are of the legal age of consent in the jurisdiction in which the study is taking place.
  • Participants who have histologically or cytologically confirmed diagnosis of Multiple Myeloma (MM), as defined by the international myeloma working group (IMWG) and have progressed on or following the last line of treatment Part 1 and Part 2: Participants who have received at least 3 prior lines of anti-myeloma treatments, , including lenalidomide, a proteasome inhibitor, and an anti-CD38 mAb either in combination or separately.
  • Part 3: Have received at least 1 prior line of treatment anti-myeloma treatments, including lenalidomide. Prior anti-CD38-containing regimen is not mandated, however no more than 70% of participants recruited may be anti-CD38 naïve
  • Participants with a history of Autologous stem cell transplant (ASCT) are eligible for study participation provided the following eligibility criteria are met:
  • Transplant was greater than (>)100 days prior to screening.
  • No active bacterial, viral, or fungal infection(s) present
  • Eastern cooperative oncology group-performance status (ECOG-PS) of 0 to 2.
  • Measurable disease defined as at least ONE of the following:
  • Serum M-protein concentration greater than (>=) 0.5 gram (g)/ deciliter (dL) (>=5 gram/liter [g/L])
  • Urine M-protein excretion >=200 milligram(mg)/24 hours (>=0.2 g/24 hours)
  • Serum free light chain (FLC) assay: involved FLC level >=10 mg/dL (>=100 milligrams per liter [mg/L]) and an abnormal serum FLC ratio (less than [<]0.26 or >1.65)
  • Have adequate organ system function as defined by the laboratory assessments
  • All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events [NCI-CTCAE], v5.0, 2017) must be Grade <=1 at the time of screening except for alopecia (any grade), neuropathy (Grade <=2), or endocrinopathy managed with replacement therapy (any grade).
  • Participants or legally authorized representative (LAR) capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
  • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
  • Is NOT a Participant of child-bearing potential (POCBP) or
  • Is a POCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
  • Part 3: Due to pomalidomide being a thalidomide analogue with a risk for embryofetal toxicity and prescribed under a pregnancy prevention/controlled distribution programme, POCBP will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or use two methods of reliable birth control (one method that is highly effective plus an additional barrier method), beginning at least 4 weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for at least 4 weeks following discontinuation of pomalidomide treatment. Thereafter, POCBP must use one contraceptive method that is highly effective (with a failure rate of less than (<)1 percentage (%) per year) for a further 3 months (total 4 months).
  • The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention
  • All POCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period
  • Participants must be 18 years of age or older, or of legal consent Age in the region where the institute is located, to sign the ICF.
  • According to the definition of IMWG [Rajkumar, 2016], participants with histologically or cytologically confirmed MM who progressed during or after last-line treatment, and who: had previously received at least 3 lines of anti-myeloma therapy, including lenalidomide, proteasome inhibitors, and anti-CD38 mAb (combination therapy or monotherapy).
  • Participants with a history of ASCT are eligible to participate in this study if they meet the following eligibility criteria: ● Transplantation was performed >100 days prior to screening ● No active bacterial, viral, or fungal infection
  • The ECOG performance status score is 0-2.
  • Measurable lesions are defined as meeting at least one of the following criteria: ● Serum M protein concentration ≥0.5 g/dL (≥5 g/L) ● Urinary M protein excretion ≥200 mg/24 hours (≥0.2 g/24 hours) ● Serum FLC detection: the involved FLC level ≥10 mg/dL (≥100 mg/L) and the serum FLC ratio is abnormal (<0.26 or >1.65)
  • Based on the laboratory assessments in Table 10, participants were determined to have the corresponding organ system functions.
  • Except for alopecia (any grade), neuropathy (≤ grade 2), or endocrine disorders managed by alternative therapy (any grade), all prior treatment-related toxicities (as defined in NCI-CTCAE, v5.0, 2017) must be ≤ grade 1 at the time of screening.
  • The contraceptive methods used by male or female participants should comply with local regulations regarding contraceptive methods for clinical research participants.
  • Participants or LARs must sign informed consent, including compliance with the requirements and restrictions set out in the ICF and this program.
Exclusion criteria
  • Diagnosis of primary Amyloid Light chain (AL) Amyloidosis, active Polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome, primary plasma cell leukemia.
  • Part 3: Active or history of venous or arterial thromboembolism within the past 3 months. Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis
  • Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with participant's safety, obtaining informed consent, or compliance with study procedures.
  • Participant is exhibiting signs of meningeal or central nervous system involvement with MM.
  • Current corneal epithelial disease except nonconfluent Superficial punctate keratitis (SPK).
  • Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.
  • Presence of malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the Principal investigator (PI) and GlaxoSmithKline (GSK) Medical Director, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (MM).Participants on active surveillance or hormone treatment for non-metastatic prostate cancer are not excluded. Participants on hormone therapy for non-metastatic breast cancer are not excluded
  • Evidence of cardiovascular risk including any of the following:
  • Evidence of current clinically significant untreated arrhythmias, including, but not limited to, clinically significant Electrocardiogram (ECG) abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree Atrioventricular (AV) block.
  • Part 1 dose escalation and Part 2 only: QT interval corrected using Fridericia's formula (QTcF) interval >480 millisecond(msec) (QT interval corrected for heart rate according to Fridericia's formula), and/or hypokalemia, and/or family history of long QT syndrome.
  • Part 1 dose expansion and Part 3: Not applicable.
  • History of MI, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within three months of screening.
  • Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • Uncontrolled hypertension
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to Unconjugated belantamab antibody / belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other Monoclonal antibodies (mAbs).
  • Active infection requiring antibiotic, antiviral, or antifungal treatment.
  • For serology of HBsAg+ at screen or within 3 months prior to first dose Japan only: must test hepatitis B e-antigen (HBeAg) and antibody to hepatitis B e-antigen (HBeAb.) Eligibility verification should be evaluated and agreed with a hepatologist (after they record the approval in the patient medical record).
  • Known Human immunodeficiency virus (HIV) infection, unless the participant can meet specific criteria.
  • Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
  • Participants with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) will be excluded unless specific criteria can be met.
  • Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible.
  • Part 1: Refractory to belantamab mafodotin (confirmed PD as per IMWG criteria while on belantamab mafodotin therapy or within 60 days of completing that treatment). Prior belantamab mafodotin is allowed if it was discontinued due to toxicity which subsequently resolved Note: Prior treatment with other anti-BCMA directed agents is allowed. Provided there is at least 6-month washout after the last dose of prior anti-BCMA therapy.
  • Part 2: Prior belantamab mafodotin therapy is not allowed. Prior treatment with other anti-BCMA directed agents is allowed provided there is at least a 6-month washout after the last doseof prior anti-BCMA therapy to start of study therapy.
  • Prior radiotherapy within 2 weeks of start of study therapy.
  • Plasmapheresis within 7 days prior to the first dose of study drug.
  • Prior allogeneic transplant is prohibited.
  • Participants who have received prior Chimeric Antigen Receptor T-cell therapy (CAR-T) therapy with lymphodepletion with chemotherapy within 3 months of screening.
  • Any major surgery (other than bone-stabilizing surgery) within 2 weeks of first dose or has not recovered fully from surgery.
  • Prior treatment with a mAb within 30 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is longer.
  • Part 1: Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including Granulocyte colony stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GMCSF), recombinant erythropoietin) or any thrombopoietin receptor agonists within 2 weeks before the first dose of study drug.
  • Part 3:Prior Unconjugated belantamab antibody, belantamab mafodotin, and pomalidomide therapy. are not allowed. Prior treatment with other anti- B-cell maturation antigen (BCMA) directed agents is allowed provided there is at least 6-month washout after the last dose of prior anti-BCMA therapy.
  • Participants must not receive live/live attenuated vaccines within 30 days prior to first dose of study treatment or whilst receiving Unconjugated belantamab antibody for at least 70 days following last study treatment.
  • Known, current drug or alcohol abuse.
  • Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective Independent Review Board (IRB) approval (by chair or designee) is allowing exception to this criterion for a specific participant
  • The diagnosis was primary AL amyloidosis, active POEMS syndrome, and plasma cell leukemia.
  • Participants must have any serious and/or unstable pre-existing medical, mental illness, or other condition (including abnormal laboratory test results) that may interfere with their safety, obtaining informed consent, or compliance with research procedures.
  • Participants exhibited signs of MM involving the meninges or central nervous system.
  • Currently suffering from corneal epithelial disease (excluding non-fusion SPK).
  • According to researchers' assessment, having cirrhosis or currently unstable hepatobiliary disease is defined as having ascites, encephalopathy, coagulation disorders, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.
  • Patients with malignant tumors other than those studied were excluded, as were participants who had maintained a disease-free status for more than 2 years, and whose treatment would not affect the evaluation of the impact of this clinical trial's treatment on their current targeted malignancy (MM). Note: Participants with cured non-melanoma skin cancer, breast cancer, or cervical carcinoma in situ were not excluded, regardless of the time elapsed since diagnosis. Participants with non-metastatic prostate cancer receiving active surveillance or hormone therapy were not excluded. Participants with non-metastatic breast cancer receiving hormone therapy were not excluded.
  • Evidence of cardiovascular risk, including any of the following: a. Evidence that the participant currently has a clinically significant untreated arrhythmia, including but not limited to clinically significant ECG abnormalities such as second-degree (Moses type II) or third-degree AV block. b. Part 1 dose escalation and Part 2 only: QTcF interval >480 ms (QT interval corrected for heart rate according to the Fridricia formula), and/or hypokalemia, and/or a family history of long QT syndrome. Part 1 dose extension and Part 3: Not applicable. c. History of MI, acute coronary syndrome (including unstable angina), coronary angioplasty, stent implantation, or bypass grafting within 3 months prior to screening. d. Heart failure of NYHA functional class III or IV. e. Uncontrolled hypertension.
  • Known immediate or delayed-type hypersensitivity or specific reactions to chemically related drugs or components of investigational treatments for belantamab/belantamab mafodotin. History of severe hypersensitivity to other monoclonal antibodies (mAbs).
  • Active infection requiring antibiotic, antiviral, or antifungal treatment.
  • Participants are known to be HIV-positive unless they meet specific criteria.
  • A recent (within the past 6 months) history of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
  • For patients who were HBsAg positive at screening or within 3 months prior to the first dose (Japan only): HBeAg and HBeAb testing is mandatory. Eligibility should be confirmed and agreed upon by a hepatologist, and approval should be recorded in the patient's medical record.
  • Participants must have a positive hepatitis C antibody test or a positive hepatitis C RNA test within 3 months prior to screening or the first administration of the study treatment, unless specific criteria are met.
  • Participants must have active kidney disease (infection, dialysis required, or any other condition that may affect participant safety). Participants with isolated proteinuria due to MM are eligible to participate in this study if they meet the criteria given in the adequate organ system function table (Table 10).
  • Part 1: Belantamab Mafodotin Refractory (PD confirmed according to IMWG criteria during or within 60 days of completing belantamab mafodotin treatment). Participants were admitted to this study if their prior belantamab mafodotin treatment was discontinued due to toxicity (subsequently resolved). Note: Participants who had previously received other anti-BCMA targeted therapies were admitted to this study if they had a washout period of at least 6 months after their last dose of their previous anti-BCMA therapy.
  • The patient had received radiation therapy within two weeks prior to the start of the treatment study.
  • Participants underwent plasma exchange within 7 days prior to the first administration of the study drug.
  • Participants had received prior CAR-T therapy with lymphocyte ablation chemotherapy within 3 months prior to screening.
  • If you have undergone any major surgery (excluding bone fixation surgery) or have not fully recovered from surgery within 2 weeks prior to the first dose, you should be aware of this.
  • Those who have received mAb treatment within 30 days prior to the first administration of the investigational drug, or who have received the investigational drug or approved systemic antimyeloma treatment (including systemic steroids) within 14 days or 5 half-lives prior to the first administration of the investigational drug (whichever is longer), are considered to have received the investigational drug or approved systemic antimyeloma treatment.
  • 20
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  • twenty one Part 1 dose escalation only: Received blood product (including platelets or red blood cells) transfusion or colony-stimulating factor (including G-CSF, GMCSF, recombinant erythropoietin) or any thrombopoietin receptor agonist within 2 weeks prior to the first administration of the study drug.
  • 21
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  • twenty two Participants must not receive a live/attenuated live vaccine within 30 days prior to the first dose of study treatment, or during belantamab treatment, or at least 70 days after the last dose of study treatment.
  • 22
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  • twenty three You are or have a family member (e.g., spouse, parent/legal guardian, sibling or child) who is a staff member of the research center or the sponsor directly involved in this study, except for specific participants who meet the criteria after obtaining prospective approval from the IRB (by the chair or designated person).

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Andrew Sochacki
Status
Recruiting
Condition(s) Treated at Site
Multiple Myeloma
Location
START Dallas Fort Worth
Fort Worth, TX, United States, 76104
Investigator
Henry Xiong
Status
Recruiting
Condition(s) Treated at Site
Multiple Myeloma