NCT03201250

Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma

Terminated Phase 1, PHASE2 Results posted Last updated 8 September 2023

What this trial tests

Phase 1, PHASE2 trial testing Cabozantinib in Multiple Myeloma in 11 participants. Terminated before completion.

Timeline

21 February 2018

Primary endpoint
12 April 2021

12 April 2021

Quick facts

Lead sponsor	University of Nebraska
Phase	Phase 1, PHASE2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	11
Start date	21 February 2018
Primary completion	12 April 2021
Estimated completion	12 April 2021
Sites	2 locations across United States

Drugs / interventions tested

• Cabozantinib (CABOZANTINIB) — full drug profile →

Conditions studied

• Multiple Myeloma — all drugs for Multiple Myeloma →
• Refractory Multiple Myeloma — all drugs for Refractory Multiple Myeloma →
• Relapsed/Refractory Multiple Myeloma — all drugs for Relapsed/Refractory Multiple Myeloma →

Sponsor

University of Nebraska

Who can join

19 and older, any sex, with Multiple Myeloma or Refractory Multiple Myeloma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Tolerated Dose (MTD) of Daily Cabozantinib Given Primary · 1 cycle (approximately 28 days)

The investigators will study three dose levels using the 3+3 algorithm. MTD will be assess with dose limiting toxicities (DLTs) based solely on adverse events that occur during cycle 1.

Group	Value	95% CI
Treatment	20

Overall Response Rate (ORR) Primary · 2 cycles (approximately 56 days)

Per International Myeloma Working Group (IMWG) Uniform Response Criteria guidelines as assessed by laboratory blood tests: Complete Response (CR), negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, \<5% plasma cells in bone marrow; Stringent Complete Response (sCR), same as CR plus normal serum free light chain (FLC) ratio and absence of clonal plasma cells; Very Good Partial Response (VGPR), serum and urine M-component still detectable by immunofixation or \>/= 90% reduction in serum M-component plus a urine M component of, 100mg per 24hrs; Partial Respons

Group	Value	95% CI
Level -1 = 20 mg	1
Level 0 = 40 mg	0
Level +1 = 60 mg	0

Response Durability Assessed by Progression Free Survival (PFS) Secondary · variable, defined by individual response durability in individual patients who would stay on therapy until disease progression

Progressive Disease (PD) is defined per International Myeloma Working Group (IMWG) Uniform Response Criteria guidelines is an increase of 25% from the lowest response value in any one or more of the following: Serum M-component and/or Urine M-component and/or in patients without a measurable serum and urine M protein level: the difference between involved and uninvolved FLC levels must be \>10mg/dL, Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas, Development of hypercalcemia attributed solely to the pl

Group	Value	95% CI
Level -1 = 20 mg	25	12 – 68
Level 0 = 40 mg	19	12 – 28

Adverse events — posted to ClinicalTrials.gov

Time frame: All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Dose Level -1 = 20 mg

Serious: 0/5 (0%)

Deaths: 1/5

Dose Level 0 = 40 mg

Serious: 2/3 (67%)

Deaths: 0/3

Dose Level +1= 60 mg

Serious: 0

Deaths: 0

Serious adverse events (4 terms)

Reaction	System	Dose Level -1 = 20 mg	Dose Level 0 = 40 mg	Dose Level +1= 60 mg
Other - Bacteremia infection	Infections and infestations	—	—	—
hypertension	Vascular disorders	—	—	—
hematuria	Renal and urinary disorders	—	—	—
Non-cardiac chest pain	General disorders	—	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	Dose Level -1 = 20 mg	Dose Level 0 = 40 mg	Dose Level +1= 60 mg
hypertension	Vascular disorders	—	—	—
hyperglycemia	Metabolism and nutrition disorders	—	—	—
anemia	Blood and lymphatic system disorders	—	—	—
platelet count decreased	Investigations	—	—	—
dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—
cardiomyopathy	Cardiac disorders	—	—	—
alanine aminotransferase increased	Investigations	—	—	—
aspartate aminotransferase increased	Investigations	—	—	—

Most-reported serious reactions: Other - Bacteremia infection, hypertension, hematuria, Non-cardiac chest pain.

Data from ClinicalTrials.gov NCT03201250 adverse events section.

Sponsor's own description

In the currently proposed phase I/II study, the investigators aim to treat patients with relapsed and/or relapsed refractory Multiple Myeloma who have progressed on carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. BDNF and its signaling in cancer.
   Malekan M, Nezamabadi SS, Samami E, Mohebalizadeh M, et al · · 2023 · cited 48× · PMID 36173463 · DOI 10.1007/s00432-022-04365-8
2. The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma.
   Paradzik T, Bandini C, Mereu E, Labrador M, et al · · 2021 · cited 28× · PMID 33799793 · DOI 10.3390/cancers13061235
3. AXL Receptor Tyrosine Kinase as a Therapeutic Target in Hematological Malignancies: Focus on Multiple Myeloma.
   Yan S, Vandewalle N, De Beule N, Faict S, et al · · 2019 · cited 23× · PMID 31694201 · DOI 10.3390/cancers11111727
4. Cabozantinib combination therapy for the treatment of solid tumors: a systematic review.
   Castellano D, Apolo AB, Porta C, Capdevila J, et al · · 2022 · cited 6× · PMID 35923927 · DOI 10.1177/17588359221108691
5. A comparative analysis of transcriptomics of newly diagnosed multiple myeloma: exploring drug repurposing.
   Giannakoulas A, Nikolaidis M, Amoutzias GD, Giannakoulas N. · · 2024 · cited 2× · PMID 38690165 · DOI 10.3389/fonc.2024.1390105