Pre-emptive Daratumumab Therapy of Minimal Residual Disease Reappearance or Biochemical Relapse in Multiple Myeloma (PREDATOR)

Pre-emptive Daratumumab Therapy of Minimal Residual Disease Reappearance or Biochemical Relapse in Multiple Myeloma (PREDATOR)

PREDATOR is a study investigating a role of preemptive daratumumab therapy for preclinical relapse or progression of multiple myeloma (MM).

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Daratumumab 20 MG/ML [Darzalex]

Detailed Description

The study is composed of two phase 2 randomized multi-center substudies:

• PREDATOR-BR: to investigate the role of daratumumab in the setting of biochemical relapse
• PREDATOR-MRD: to investigate the role of daratumumab in minimal residual disease (MRD) reappearance

• Study Type: Interventional
• Enrollment (Anticipated): 274
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Krzysztof Jamroziak, MD, PhD; Phone Number: +48 504 065 262; Email: k.m.jamroziak@gmail.com
• Study Contact Backup: Name: Dominik Dytfeld, MD, PhD; Phone Number: +48 602 464 708; Email: dytfeld@me.com

Study Locations

• Poland
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-776
      • Recruiting
      • Instytut Hematologii i Transfuzjologii
      • Contact: Krzysztof Jamroziak, MD, PhD; Phone Number: +48 22 349 64 78; Email: k.m.jamroziak@gmail.com
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 60-569
      • Recruiting
      • Szpital Kliniczny Przemienienia Pańskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu; Oddział Hematologii i Transplantacji Szpiku
      • Contact: Dominik Dytfeld, MD, PhD; Phone Number: +48 602464708; Email: dytfeld@me.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

PREDATOR-BR:

Inclusion Criteria:

1. Patients with diagnosed symptomatic MM who have completed one or two prior lines of therapy; single or tandem autologous stem cell transplant is not considered a separate line of therapy and is not mandatory; and have achieved at least PR to last line of therapy, and who experience asymptomatic biochemical progression not meeting criteria for SPR.
2. Males and females ≥18 years of age.
3. Life expectancy of more than 3 months.
4. ECOG performance status of 0-2.
5. Adequate hepatic function, with bilirubin ≤1.5 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.
6. ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL, platelet count ≥75 x 109/L.
7. Calculated creatinine clearance (by Cockroft-Gault) ≥50 mL/min (this equation is as follows: Creatinine clearance in ml/min: (140 - age) x body weight (kg) / 72 x plasma creatinine (mg/dL); multiplied by 0.85 for women) or serum creatinine below 2 g/dL.
8. Negative pregnancy test (serum βHCG) for women of childbearing potential (including pre-menopausal women who have had a tubal ligation) and for all women not meeting the definition of postmenopausal (≥ 24 months of amenorrhea), and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential.
9. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the study.
10. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
11. Voluntary written informed consent.

Exclusion Criteria:

1. Potential subjects with evidence of progressive disease (CRAB symptoms) as per IMWG criteria.
2. Patient with SPR - significant paraprotein relapse defined as doubling of the M-component in two consecutive measurements separated by < 2 months; or an increase in the absolute levels of serum M protein by 1g/dl, or urine M protein by 500mg /24h, or involved serum FLC level by 20mg/dl (plus an abnormal FLC ratio) in two consecutive measurements separated by < 2 months.
3. Patients who have already started or received post-transplant maintenance or consolidation treatment.
4. Subject has received daratumumab or other anti-CD38 therapies previously.
5. Patients not able to tolerate daratumumab or required concomitant medication and procedures.
6. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
7. Known moderate or severe persistent asthma, or a history of asthma within the last 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 to participate in the study).
8. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
9. Plasma cell leukemia.
10. Waldenström's macroglobulinemia.
11. CNS involvement.
12. Pregnant or lactating females.
13. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.
14. Major surgery within 3 weeks prior to first dose. Kyfoplasty is not considered as a major surgery.
15. Myocardial infarction within 3 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
16. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening.
17. Patient who in investigator's opinion is unable to comply with the protocol requirements.
18. Uncontrolled hypertension or diabetes.
19. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to enter the study.
20. Active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
21. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone.
22. Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.

PREDATOR-MRD:

Inclusion Criteria:

1. Patients with diagnosed symptomatic MM who have completed one or two prior lines of therapy; single or tandem autologous stem cell transplant is not considered a separate line of therapy and is not mandatory; and have achieved CR with negative MRD to the last line of therapy and who remain in CR MRD negative. The last response assessment confirming CR MRD negative status based on assessment of bone marrow sample using flow cytometry with sensitivity of at least 10-5 needs to be performed not earlier than 3 months before inclusion to the study.
2. Males and females ≥18 years of age.
3. Life expectancy of more than 3 months.
4. ECOG performance status of 0-2.
5. Adequate hepatic function, with bilirubin ≤1.5 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.
6. ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL, platelet count ≥75 x 109/L.
7. Calculated creatinine clearance (by Cockroft-Gault) ≥50 mL/min (this equation is as follows: Creatinine clearance in ml/min: (140 - age) x body weight (kg) / 72 x plasma creatinine (mg/dL); multiplied by 0.85 for women) or serum creatinine below 2 g/dL.
8. Negative pregnancy test (serum βHCG) for women of childbearing potential (including pre-menopausal women who have had a tubal ligation) and for all women not meeting the definition of postmenopausal (≥ 24 months of amenorrhea), and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential
9. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the study.
10. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
11. Voluntary written informed consent.

Exclusion criteria:

1. Potential subjects with evidence of progressive disease (CRAB symptoms) as per IMWG criteria.
2. Patient with SPR - significant paraprotein relapse defined as doubling of the M-component in two consecutive measurements separated by < 2 months; or an increase in the absolute levels of serum M protein by 1g/dl, or urine M protein by 500mg /24h, or involved serum FLC level by 20mg/dl (plus an abnormal FLC ratio) in two consecutive measurements separated by < 2 months.
3. Patients who have already started or received post-transplant maintenance or consolidation treatment.
4. Subject has received daratumumab or other anti-CD38 therapies previously.
5. Patients not able to tolerate daratumumab or required concomitant medication and procedures.
6. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
7. Known moderate or severe persistent asthma, or a history of asthma within the last 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 to participate in the study).
8. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
9. Plasma cell leukemia.
10. Waldenström's macroglobulinemia.
11. CNS involvement.
12. Pregnant or lactating females.
13. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.
14. Major surgery within 3 weeks prior to first dose. Kyfoplasty is not considered as a major surgery.
15. Myocardial infarction within 3 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
16. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12- lead ECG during screening.
17. Patient who in investigator's opinion is unable to comply with the protocol requirements.
18. Uncontrolled hypertension or diabetes.
19. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to enter the study.
20. Active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
21. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone.
22. Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PREDATOR-BR Cohort A; n=46, Daratumumab 20 MG/ML [Darzalex], 16 mg/kg body weight administered as an intravenous infusion	Drug: Daratumumab 20 MG/ML [Darzalex]; Daratumumab dose 16 mg/kg body weight to be administered as an IV infusion. treatment given until clinical progression or SPR but no longer than 73 weeks; Other Names: Darzalex
No Intervention: PREDATOR-BR Cohort B; n=46, Control Group, Observation (no treatment)
Experimental: PREDATOR-MRD Cohort A; n=59, Daratumumab 20 MG/ML [Darzalex], 16 mg/kg body weight administered as an intravenous infusion	Drug: Daratumumab 20 MG/ML [Darzalex]; Daratumumab dose 16 mg/kg body weight to be administered as an IV infusion. treatment given until clinical progression or SPR but no longer than 73 weeks; Other Names: Darzalex
No Intervention: PREDATOR-MRD Cohort B; n=59, Control Group, Observation (no treatment)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival (ESF)	To compare (EFS) between daratumumab arm and observation arm after randomization of patients with biochemical relapse of Multiple Myeloma and MRD reappearance in Multiple Myeloma	from randomization till the date of development clinical relapse or death from any cause; up to 129 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	ORR as determined by Investigator evaluation, defined as the percentage of subjects achieving an objective response (i.e. partial response or better), using IMWG Consensus Panel 1 response criteria	from randomization till progression or death from any cause, up to 129 weeks
Overall Survival	To compare overall survival between arms	throughout the duration of the study, no longer than 6 years

Collaborators and Investigators

• Sponsor: Polish Myeloma Consortium
• Collaborators: Janssen-Cilag Ltd.; Bioscience, S.A.
• Investigators: Principal Investigator: Krzysztof Jamroziak, MD, PhD, Polish Myeloma Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2018
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: September 20, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 5, 2018

Study Record Updates

• Last Update Posted (Actual): January 3, 2019
• Last Update Submitted That Met QC Criteria: January 2, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplastic Processes; Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasm, Residual; Antineoplastic Agents; Daratumumab
• Other Study ID Numbers: PMC008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No