A Study of Daratumumab With Pomalidomide, Dexamethasone, and All-Transretinoic Acid in Patients With Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Multi-Center Phase 2 Study of Daratumumab With Pomalidomide and Dexamethasone in Combination With All-Transretinoic Acid in Patients With Multiple Myeloma Previously Exposed to Daratumumab-Based Regimens

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04700176
• Other study ID #: Pro2020-0280
• Status: Terminated
• Phase: Phase 2
• Start date: May 2, 2022
• Est. completion date: November 15, 2023

Study information

• Verified date: January 2024
• Source: Hackensack Meridian Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test the safety and efficacy of the study drug daratumumab, when given together with Pomalidomide, Dexamethasone, and All-Transretinoic Acid (ATRA).

Description:

This is a multi-institution phase II study of ATRA in combination with fixed dose Daratumumab, Pomalidomide and Dex for a total of 33 patients in patients with relapsed multiple myeloma who have progressed on the combination of Dara + Len + Dex. There will also be an exploratory cohort with an additional 10 patients who have progressed on the combination of Dara + Pom + Dex.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: November 15, 2023
• Est. primary completion date: November 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Documented multiple myeloma

2. For cohort A, patients must have been previously exposed to Dara+Len+Dex and must have achieved at least stable disease to this combination.

3. For cohort B, patients must have been exposed to Dara + Pom + Dex and must have achieved at least stable disease to this combination.

4. Histologically confirmed and relapsed multiple myeloma with measurable disease,

defined by at least one of the following:

1. Serum monoclonal protein =0.5 g/dL;

2. Monoclonal protein in the urine on 24-hour electrophoresis =200 mg;

3. Serum immunoglobulin free light chain (FLC) =10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal;

4. New of progressing biopsy proven plasmacytoma on exam or imaging; or

5. Bone marrow plasma cells =20%;

5. Cycle 1 day 1 of study treatment must be within 3 months of last exposure to Daratumumab.

6. Life expectancy >3 months

7. ECOG PS 0-2

8. Age =18

9. Adequate organ function, including bone marrow, renal, hepatic, pulmonary, and cardiac function based on the last assessment performed within the Screening Period, defined

as:

1. Absolute neutrophil count (ANC) =1,000/µL;

2. Platelet count =50,000/µL, (=30,000/µL if bone marrow plasma cells are =50% of cellularity);

3. Hemoglobin =7.5g/dL;

4. Creatinine clearance =60 mL/min (assessed as glomerular filtration rate using the Cockcroft-Gault formula);

5. Alanine aminotransferase or aspartate aminotransferase <3 x upper limit of normal (ULN);

6. Total bilirubin <2 x ULN (except for patients with Gilbert's syndrome confirmed by UGT1A1 mutation);

7. Left ventricular ejection fraction =50% as assessed by echocardiography or multi-gated acquisition (MUGA) scan; and

8. Must have a minimum level of pulmonary reserve defined as Grade <2 dyspnea and pulse oxygenation =92% on room air;

10. Prior to first dose of study drug, a woman must be either:

• Not of childbearing potential: premenarchal; postmenopausal (>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone level >40 IU/L or mIU/mL]); permanently sterilized (eg, bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy
• Of childbearing potential and practicing a highly effective method of birth control for 4 weeks before initiating study treatment that is consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject) Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche)
• a woman must begin a highly effective method of birth control, as described above.

11. A woman of childbearing potential must have 2 negative serum (ß human chorionic gonadotropin) or urine pregnancy tests during screening, the first one within 28 days prior to the first dose of study drug and the second within 24 hours prior to the first dose of study drug.

12. 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, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug.

13. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol and referenced in the informed consent form (ICF).

Exclusion Criteria:

1. Major concurrent illness or organ dysfunction

2. Active GVHD requiring systemic corticosteroids in a subject who previously received allogeneic-SCT.

3. Cord compression or CNS involvement

4. Recent/Prior active malignancy requiring active therapy 2 years prior to enrollment excluding non-melanoma skin cancer.

5. Prior life-threatening hypersensitivity to daratumumab or an IMiD

6. Plasma cell leukemia

7. Pregnant or lactating females

8. Men donating sperm during study

9. Seropositive for human immunodeficiency virus (HIV)

10. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, 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

11. 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)

12. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Daratumumab
During 28-day treatment cycles, patients will receive Dara 16 mg/kg intravenously (IV) at their current dose upon enrollment onto the study depending on their cycle. They will receive Dara depending on the cycle they are in. If they are on cycles 1-2 then they will receive Dara 16 mg/kg IV on days 1,8,15,22; if they are on cycles 3-6 they will receive Dara 16 mg/kg on days 1 and 15; and if they are on cycle 7 or beyond they will receive Dara 16 mg/kg on day 1.
• Pomalidomide
Pomalidomide will be administered at the patient's currently tolerated dose (4,3, or 2 mg po daily) on days 1-21
• All-trans retinoic acid
ATRA will be administered in a divided dose of twice daily as an oral formulation at 45mg/m2/day for 3 days. The first administration of ATRA will be given in the morning, two days before the scheduled Dara infusion. The last administration of ATRA will be given in the evening of the day that Dara was administered
• Dexamethasone
Dexamethasone will be administered at 40 mg once weekly on days 1,8,15 for patients 75 years old and younger and at 20 mg once weekly on days 1,8,15 for patients older than 75.

Locations

Country	Name	City	State
United States	John Theurer Cancer Center	Hackensack	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Hackensack Meridian Health	Janssen, LP

Country where clinical trial is conducted

United States, 

References & Publications (19)

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* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (Cohort A)	To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Len + Dex (Cohort A)	12 Months
Primary	Incidence of Adverse Events	Incidence of Adverse Events in the combination of Dara + Pom + Dex + ATRA using CTCAE V5 criteria.	12 Months
Secondary	Objective Response Rate (Cohort B)	To determine the ORR of the combination of Dara + Pom + Dex + ATRA in patients progressing on Dara + Pom + Dex	12 Months
Secondary	Best Stringent Complete Response	To determine the best stringent complete response (sCR)/CR/near CR (nCR) and >/= very good partial response (VGPR) rates.	12 Months
Secondary	Incidence of Treatment-Emergent Adverse Events	To define the toxicity using CTCAE V5 criteria.	12 Months
Secondary	Minimal Residual Disease Evaluation	To evaluate the status of minimal residual disease (MRD) in patients who achieve sCR, CR, or nCR.	12 Months
Secondary	Time on Study (TOS)	Duration from start of study treatment to end of study	12 Months
Secondary	Duration of Response (DOR)	Duration from treatment response to progression	12 Months
Secondary	Time To Progression (TTP)	Duration from start of study treatment to progression	12 Months
Secondary	Progression-Free Survival (PFS)	Duration from start of study treatment to PD or death [regardless of cause], whichever comes first	12 Months
Secondary	Overall Survival (OS)	Duration from start of study treatment to death	12 Months