Daratumumab in Combination With ATRA

NCT02751255 | Completed Phase 1 DMC

• 1 other identifier: 2015-003862-10
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (3)

• MTD

  To determine the maximum tolerated dose (MTD) of daratumumab combined with ATRA. MTD is defined during the first treatment cycle (4 weeks).

  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.

  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).

  phase 1, during the first treatment cycle (28 days)

Secondary Outcomes (6)

• Incidence of severe adverse events

  Phase 1 and 2, throughout treatment, estimated to be 8 months

• Progression-free survival (PFS)

  phase 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.

• overall survival (OS)

  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

  phase 1 and 2, every 28 days, until last treatment received, estimated to be 8 months

• prognostic factors for PFS

  phase 1 and 2, all patients will be followed until 1 year after the last patient has received the last infusion of daratumumab.

Study Arms (1)

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).

Drug: all-trans retinoic acid (ATRA)

Interventions

all-trans retinoic acid (ATRA) DRUG

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).

Also known as: ATRA

daratumumab--> daratumumab + ATRA

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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

You may not qualify if:

• 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.
• 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.
• b) 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.

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Erasmus Medical Center: collaborator
• UMC Utrecht: collaborator
• University of Turin, Italy: collaborator
• Vejle Hospital: collaborator

Study Sites (1)

VU University Medical Center

Amsterdam, North Holland, 1081HV, Netherlands

Location

Related Publications (4)

• 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.

  PMID: 26864107 RESULT

• Lokhorst 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.

  PMID: 26308596 RESULT

• Nijhof 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.

  PMID: 25975191 RESULT

• Frerichs 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.

  PMID: 34625791 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Tretinoin

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Niels W van de Donk, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hematologist

Study Record Dates

• First Submitted: April 4, 2016
• First Posted: April 26, 2016
• Study Start: July 6, 2016
• Primary Completion: October 18, 2022
• Study Completion: October 18, 2022
• Last Updated: April 28, 2023

Record last verified: 2023-04

Locations

NL (1)