Multiple MyelomaPhase 1/2DARA/ATRANCT02751255
Daratumumab in Combination With ATRA
A Phase 1/2 study testing all-trans retinoic acid (ATRA) in people with Multiple Myeloma, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial summary
Multiple myeloma (MM) patients who develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months, indicating that new agents are urgently needed. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- all-trans retinoic acid (ATRA)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteNetherlands
- Study dates
- 6 Jul 2016to 18 Oct 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥18 years
- Subject must have documented multiple myeloma as defined by the criteria below:
- Monoclonal plasma cells in the bone marrow ≥10% at some point in their disease history or presence of a biopsy proven plasmacytoma.
- Measurable disease as defined by any of the following:
- Serum monoclonal paraprotein (M-protein) level ≥5 g/L (0.5 g/dL); or urine M-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A)
- Relapsed from or refractory to 2 or more different prior therapies, including immunomodulatory drugs (IMiDs; eg, thalidomide, lenalidomide) and proteasome inhibitors, chemotherapy-based regimens, or autologous stem cell transplantation (ASCT).
Show all 11Show fewer
- Relapse is defined as progression of disease after an initial response (MR or better) to previous treatment, more than 60 days after cessation of treatment
- Refractory disease is defined as <25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment
- WHO performance 0, 1, or 2
- Life expectancy at least 3 months
- Written informed consent
Who cannot join
- Subject has received daratumumab or other anti-CD38 therapies, within 6 months before start of treatment (however, patients treated with daratumumab monotherapy in compassionate use program or after European Medicines Agency (EMA) approval, and have progressive disease during daratumumab after previous response, or unresponsive disease to daratumumab [progressive disease after cycle 1, less than minimal response after cycle 2, or less than partial response after cycle 3], may be included in Part B)
- Non-secretory myeloma
- Systemic amyloid light-chain (AL) amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia
- Subject has known meningeal involvement of multiple myeloma
- Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment.
- Subject has previously received an allogeneic stem cell transplantation within 1 year before the date of registration and has not used immunosuppressive drugs within one months before the date of registration.
Show all 23Show fewer
- Inadequate marrow reserve as defined by a platelet count <30 x 109/L or an absolute neutrophil count <1.0 x 109/L
- a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
- Subject has known 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).
- Subject has clinically significant cardiac disease, including:
- Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
- Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Version 4 Grade 2 or higher) or clinically significant ECG abnormalities.
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.
- Significant hepatic dysfunction (total bilirubin 3 times normal value or transaminases 3 times normal value), unless related to myeloma
- Creatinine clearance <20 ml/min.
- Known hypersensitivity to components of the investigational product or severe allergic or anaphylactic reactions to humanized products.
- Subject has any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) 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.
- Subject is known to be seropositive for human immunodeficiency virus (HIV) or have active hepatitis B or hepatitis C.
- History of active malignancy during the past 5 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 5 years.
- Subject is known or suspected of not being able to comply with the study protocol (eg, 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 (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
- Pregnant or lactating females
- Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab. For patients in the US, the use of a double-barrier method is also considered adequate.
- Sensory or motor neuropathy of ≥grade 3.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
VU University Medical Center
Amsterdam, North Holland, 1081HV
About this study
Official title: A Phase 1 and Phase 2 Study of Daratumumab in Combination With All-trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma
Multiple myeloma (MM) patients who develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months, indicating that new agents are urgently needed. Recent studies have shown that daratumumab as a single agent is effective and well tolerated in these heavily pretreated MM patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients will develop progressive disease during daratumumab therapy.
The investigators have demonstrated that levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59 determine the susceptibility of the MM cells towards daratumumab. In addition, MM cells have lower CD38 expression levels and higher levels of CD55/CD59 at the time of progression. Importantly, all-trans retinoic acid (ATRA) upregulates CD38 levels and downregulates CD55/CD59 levels on MM cells, both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug. These alterations in expression explain the strong synergy between ATRA and daratumumab, both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease.
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients.
Read the detailed description
Multiple myeloma (MM) patients that develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months. This clearly illustrates that new anti-MM agents are needed with different mechanisms of action.
Importantly, daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients, also those achieving complete response, will develop progressive disease during daratumumab therapy. Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59. At the time of progression, there is a reduced level of CD38 on the MM cells, whereas CD55 and CD59 levels are increased. This indicates that these factors are also involved in the development of daratumumab-resistant disease.
Importantly, ATRA upregulates CD38 levels and downregulates CD55/CD59 levels on MM cells, both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug. These alterations in expression explain the strong synergy between ATRA and daratumumab, both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease.
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients. The investigators will treat relapsed/refractory MM patients in two stages. The first stage (part A) consists of treatment with daratumumab monotherapy. In case these patients have progressive disease after cycle 1, less than minimal response after cycle 2, or less than partial response after cycle 3 (unless ongoing response) to single agent daratumumab, or in case these patients progress during daratumumab therapy after previous response, then ATRA will be added to daratumumab (part B).
The aims of this study are to develop a safe ATRA and daratumumab combination suitable for clinical use and evaluation in subsequent randomized clinical trials. To this end, the maximum tolerated dose (MTD) of ATRA and daratumumab will be determined for patients with relapsed/refractory disease, who were treated with daratumumab but failed to achieve a partial response, or developed progressive disease during daratumumab treatment. This will be followed by a second part in which the investigators will examine the effectivity and toxicity profile of the combination at the MTD.
- Conditions
- Multiple Myeloma
- Being tested
- all-trans retinoic acid (ATRA)
- Medical subject headings
- Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
all-trans retinoic acid (ATRA)Drug
Also called ATRA
Phase 1 and 2: daratumumab 16 mg/kg, first 8 infusions are given weekly, then 8 infusions every 3 weeks, then every 4 weeks until progression Phase 1: ATRA 15, 30, or 45 mg/m2/day for 3 days. Phase 2: ATRA will be administered twice daily as an oral formulation at the MTD dose, or if no MTD is reached, at the dose of 45 mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled daratumumab infusion. The last administration of ATRA will be given in the evening of the day that daratumumab was administered (days -2, -1, and 0; day 0 is the day of daratumumab infusion).
| Study group | Role | What they receive |
|---|---|---|
| daratumumab--> daratumumab + ATRA | Experimental | In part A of the study patients will be treated with daratumumab as a single agent. In case patients have progressive disease after cycle 1, or in case patients achieve less than minimal response after cycle 2, or patients achieve less than PR after cycle 3, or in case patients experience progression during daratumumab therapy after having obtained a response, then ATRA will be added to daratumumab (part B). Receives: Drug: all-trans retinoic acid (ATRA) |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD
To determine the maximum tolerated dose (MTD) of daratumumab combined with ATRA. MTD is defined during the first treatment cycle (4 weeks).
Measured: phase 1, during the first treatment cycle (28 days)
overall response rate
To investigate the efficacy of daratumumab combined with ATRA at the RDL, as determined by the overall response rate. This will be determined through study completion.
Measured: Phase 2, every 28 days, until last treatment received, estimated to be 8 months
RDL
To determine the recommended phase 2 dose level (RDL) of daratumumab combined with ATRA. RDL is defined during the first treatment cycle (4 weeks).
Measured: phase 1, during the first treatment cycle (28 days)
Secondary outcomes (6)
Incidence of severe adverse events
evaluation of severe adverse events (SAEs) through study completion. The analysis of treatment toxicity will be done primarily by tabulation of the incidence of adverse events CTCAE grade 2 or more by treatment cycle. Data from all subjects who receive any study drug will be included in the safety analyses. In the by-subject analysis, a subject having the same event more than once will be counted only once. Adverse events will be summarized by worst CTCAE grade.
Measured: Phase 1 and 2, throughout treatment, estimated to be 8 months
Progression-free survival (PFS)
Progression-free survival is defined as time from registration until progression or death, whichever comes first. Actuarial survival curves for PFS will be computed using the Kaplan-Meier method, and 95% confidence interval (CI) will be constructed.
Measured: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
overall survival (OS)
OS will be determined until study completion
Measured: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for response
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Measured: phase 1 and 2, every 28 days, until last treatment received, estimated to be 8 months
prognostic factors for PFS
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Measured: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for OS
This includes beta2 microglobulin (mg/L), cytogenetic abnormalities as determined by fluorescence in situ hybridization (FISH), thrombocyte counts, albumin, and LDH. These prognostic factors will be determined at baseline, before the first daratumumab infusion.
Measured: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2016 (estimated)
- Study start6 Jul 2016
- Primary completion18 Oct 2022
- Study completion18 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Multiple MyelomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, UMC Utrecht, University of Turin, Italy, Vejle Hospital
- Responsible party
- Principal investigator, WCJ van de Donk, Amsterdam UMC, location VUmc
- Investigators
- Niels W van de Donk, MD PhD, Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02751255
- Sponsor's protocol ID
- 2015-003862-10
- Other IDs
- 2015
- Acronym
- DARA/ATRA
- Status last verified
- Apr 2023
- First submitted
- 4 Apr 2016
- Last updated
- 28 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
van de Donk NW, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK, Lokhorst HM, Parren PW. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016 Mar;270(1):95-112. doi: 10.1111/imr.12389.
PubMed 26864107Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26.
PubMed 26308596Nijhof IS, Groen RW, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J, de Jong-Korlaar R, Yuan H, Noort WA, Klein SK, Martens AC, Doshi P, Sasser K, Mutis T, van de Donk NW. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015 Oct;29(10):2039-49. doi: 10.1038/leu.2015.123. Epub 2015 May 15.
PubMed 25975191Frerichs KA, Minnema MC, Levin MD, Broijl A, Bos GMJ, Kersten MJ, Mutis T, Verkleij CPM, Nijhof IS, Maas-Bosman PWC, Klein SK, Zweegman S, Sonneveld P, van de Donk NWCJ. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021 Dec 14;5(23):5128-5139. doi: 10.1182/bloodadvances.2021005220.
PubMed 34625791
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 and Phase 2 Study of Daratumumab in Combination With All-trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma
- ClinicalTrials.gov ID
- NCT02751255
- Acronym / sponsor ID
- DARA/ATRA / 2015-003862-10
- Conditions
- Multiple Myeloma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, UMC Utrecht, University of Turin, Italy, Vejle Hospital
- Study start
- 6 Jul 2016 (actual)
- Primary completion
- 18 Oct 2022 (actual)
- Study completion
- 18 Oct 2022 (actual)
- First posted
- 26 Apr 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multiple myeloma (MM) patients who develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months, indicating that new agents are urgently needed. Recent studies have shown that daratumumab as a single agent is effective and well tolerated in these heavily pretreated MM patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients will develop progressive disease during daratumumab therapy.
The investigators have demonstrated that levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59 determine the susceptibility of the MM cells towards daratumumab. In addition, MM cells have lower CD38 expression levels and higher levels of CD55/CD59 at the time of progression. Importantly, all-trans retinoic acid (ATRA) upregulates CD38 levels and downregulates CD55/CD59 levels on MM cells, both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug. These alterations in expression explain the strong synergy between ATRA and daratumumab, both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease.
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients.
Detailed description
Multiple myeloma (MM) patients that develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months. This clearly illustrates that new anti-MM agents are needed with different mechanisms of action.
Importantly, daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients, also those achieving complete response, will develop progressive disease during daratumumab therapy. Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59. At the time of progression, there is a reduced level of CD38 on the MM cells, whereas CD55 and CD59 levels are increased. This indicates that these factors are also involved in the development of daratumumab-resistant disease.
Importantly, ATRA upregulates CD38 levels and downregulates CD55/CD59 levels on MM cells, both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug. These alterations in expression explain the strong synergy between ATRA and daratumumab, both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease.
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients. The investigators will treat relapsed/refractory MM patients in two stages. The first stage (part A) consists of treatment with daratumumab monotherapy. In case these patients have progressive disease after cycle 1, less than minimal response after cycle 2, or less than partial response after cycle 3 (unless ongoing response) to single agent daratumumab, or in case these patients progress during daratumumab therapy after previous response, then ATRA will be added to daratumumab (part B).
The aims of this study are to develop a safe ATRA and daratumumab combination suitable for clinical use and evaluation in subsequent randomized clinical trials. To this end, the maximum tolerated dose (MTD) of ATRA and daratumumab will be determined for patients with relapsed/refractory disease, who were treated with daratumumab but failed to achieve a partial response, or developed progressive disease during daratumumab treatment. This will be followed by a second part in which the investigators will examine the effectivity and toxicity profile of the combination at the MTD.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| daratumumab--> daratumumab + ATRA | Experimental | Drug: all-trans retinoic acid (ATRA)In part A of the study patients will be treated with daratumumab as a single agent. In case patients have progressive disease after cycle 1, or in case patients achieve less than minimal response after cycle 2, or patients achieve less than PR after cycle 3, or in case patients experience progression during daratumumab therapy after having obtained a response, then ATRA will be added to daratumumab (part B). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Age ≥18 years
- Subject must have documented multiple myeloma as defined by the criteria below:
- Serum monoclonal paraprotein (M-protein) level ≥5 g/L (0.5 g/dL); or urine M-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A)
- Relapsed from or refractory to 2 or more different prior therapies, including immunomodulatory drugs (IMiDs; eg, thalidomide, lenalidomide) and proteasome inhibitors, chemotherapy-based regimens, or autologous stem cell transplantation (ASCT).
- WHO performance 0, 1, or 2
Key exclusion criteria (23 listed)
- Subject has received daratumumab or other anti-CD38 therapies, within 6 months before start of treatment (however, patients treated with daratumumab monotherapy in compassionate use program or after European Medicines Agency (EMA) approval, and have progressive disease during daratumumab after previous response, or unresponsive disease to daratumumab [progressive disease after cycle 1, less than minimal response after cycle 2, or less than partial response after cycle 3], may be included in Part B)
- Non-secretory myeloma
- Systemic amyloid light-chain (AL) amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia
- Subject has known meningeal involvement of multiple myeloma
- Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| all-trans retinoic acid (ATRA)Also: ATRAPhase 1 and 2: daratumumab 16 mg/kg, first 8 infusions are given weekly, then 8 infusions every 3 weeks, then every 4 weeks until progression Phase 1: ATRA 15, 30, or 45 mg/m2/day for 3 days. Phase 2: ATRA will be administered twice daily as an oral formulation at the MTD dose, or if no MTD is reached, at the dose of 45 mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled daratumumab infusion. The last administration of ATRA will be given in the evening of the day that daratumumab was administered (days -2, -1, and 0; day 0 is the day of daratumumab infusion). | Drug | daratumumab--> daratumumab + ATRA |
Primary outcome
MTD
Time frame: phase 1, during the first treatment cycle (28 days)
To determine the maximum tolerated dose (MTD) of daratumumab combined with ATRA. MTD is defined during the first treatment cycle (4 weeks).
overall response rate
Time frame: Phase 2, every 28 days, until last treatment received, estimated to be 8 months
To investigate the efficacy of daratumumab combined with ATRA at the RDL, as determined by the overall response rate. This will be determined through study completion.
RDL
Time frame: phase 1, during the first treatment cycle (28 days)
To determine the recommended phase 2 dose level (RDL) of daratumumab combined with ATRA. RDL is defined during the first treatment cycle (4 weeks).
6 secondary outcomes
Incidence of severe adverse events
Time frame: Phase 1 and 2, throughout treatment, estimated to be 8 months
Progression-free survival (PFS)
Time frame: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
overall survival (OS)
Time frame: phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for response
Time frame: phase 1 and 2, every 28 days, until last treatment received, estimated to be 8 months
prognostic factors for PFS
Time frame: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
prognostic factors for OS
Time frame: phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2023.
- Results publication: PubMed 26864107van de Donk NW, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK, Lokhorst HM, Parren PW. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016 Mar;270(1):95-112. doi: 10.1111/imr.12389.
- Results publication: PubMed 26308596Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26.
- Results publication: PubMed 25975191Nijhof IS, Groen RW, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J, de Jong-Korlaar R, Yuan H, Noort WA, Klein SK, Martens AC, Doshi P, Sasser K, Mutis T, van de Donk NW. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015 Oct;29(10):2039-49. doi: 10.1038/leu.2015.123. Epub 2015 May 15.
- Derived from this study: PubMed 34625791Frerichs KA, Minnema MC, Levin MD, Broijl A, Bos GMJ, Kersten MJ, Mutis T, Verkleij CPM, Nijhof IS, Maas-Bosman PWC, Klein SK, Zweegman S, Sonneveld P, van de Donk NWCJ. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021 Dec 14;5(23):5128-5139. doi: 10.1182/bloodadvances.2021005220.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Niels W van de Donk, MD PhD principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing all-trans retinoic acid (ATRA) in people with Multiple Myeloma, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MTD (time frame: phase 1, during the first treatment cycle (28 days)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02751255, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2023.