ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study

Marit A C Vermunt; Debbie G J Robbrecht; Lot A Devriese; Julie M Janssen; Bas Thijssen; Marianne Keessen; Maarten van Eijk; Rob Kessels; Ferry A L M Eskens; Jos H Beijnen; Niven Mehra; Andries M Bergman

doi:10.1002/cnr2.1367

ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study

Marit A C Vermunt
, Debbie G J Robbrecht
, Lot A Devriese
, Julie M Janssen
, Bas Thijssen
, Marianne Keessen
, Maarten van Eijk
, Rob Kessels
, Ferry A L M Eskens
, Jos H Beijnen
, Niven Mehra
, Andries M Bergman

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).

AIM: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.

METHODS: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.

RESULTS: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.

CONCLUSION: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.

Original language	English
Article number	e1367
Pages (from-to)	1-9
Journal	Cancer reports (Hoboken, N.J.)
Volume	4
Issue number	4
Early online date	12 Mar 2021
DOIs	https://doi.org/10.1002/cnr2.1367
Publication status	Published - Aug 2021

Keywords

chemotherapy
clinical trials
drug discovery and delivery
prostate cancer

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Cancer Reports - 2021 - Vermunt - ModraDoc006 an oral docetaxel formulation in combination with ritonavir ModraDoc006 r Final published version, 1.63 MBLicence: CC BY

Cite this

Vermunt, M. A. C., Robbrecht, D. G. J., Devriese, L. A., Janssen, J. M., Thijssen, B., Keessen, M., van Eijk, M., Kessels, R., Eskens, F. A. L. M., Beijnen, J. H., Mehra, N., & Bergman, A. M. (2021). ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study. Cancer reports (Hoboken, N.J.), 4(4), 1-9. Article e1367. https://doi.org/10.1002/cnr2.1367

@article{1f4d1606ecd4451bbcc9a7b79debcbcd,

title = "ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study",

abstract = "BACKGROUND: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).AIM: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.METHODS: mCRPC patients, treatment na{\"i}ve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.RESULTS: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50\% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.CONCLUSION: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.",

keywords = "chemotherapy, clinical trials, drug discovery and delivery, prostate cancer",

author = "Vermunt, \{Marit A C\} and Robbrecht, \{Debbie G J\} and Devriese, \{Lot A\} and Janssen, \{Julie M\} and Bas Thijssen and Marianne Keessen and \{van Eijk\}, Maarten and Rob Kessels and Eskens, \{Ferry A L M\} and Beijnen, \{Jos H\} and Niven Mehra and Bergman, \{Andries M\}",

note = "Funding Information: The authors thank all patients and their families for participation in the trial. ModraDoc006 tablets were produced and provided by Modra Pharmaceuticals B.V. This study was financially supported by Modra Pharmaceuticals B.V. Publisher Copyright: {\textcopyright} 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.",

year = "2021",

month = aug,

doi = "10.1002/cnr2.1367",

language = "English",

volume = "4",

pages = "1--9",

journal = "Cancer reports (Hoboken, N.J.)",

issn = "2573-8348",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

}

Vermunt, MAC, Robbrecht, DGJ, Devriese, LA, Janssen, JM, Thijssen, B, Keessen, M, van Eijk, M, Kessels, R, Eskens, FALM, Beijnen, JH, Mehra, N & Bergman, AM 2021, 'ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study', Cancer reports (Hoboken, N.J.), vol. 4, no. 4, e1367, pp. 1-9. https://doi.org/10.1002/cnr2.1367

ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study. / Vermunt, Marit A C; Robbrecht, Debbie G J; Devriese, Lot A et al.
In: Cancer reports (Hoboken, N.J.), Vol. 4, No. 4, e1367, 08.2021, p. 1-9.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients

T2 - A phase Ib study

AU - Vermunt, Marit A C

AU - Robbrecht, Debbie G J

AU - Devriese, Lot A

AU - Janssen, Julie M

AU - Thijssen, Bas

AU - Keessen, Marianne

AU - van Eijk, Maarten

AU - Kessels, Rob

AU - Eskens, Ferry A L M

AU - Beijnen, Jos H

AU - Mehra, Niven

AU - Bergman, Andries M

N1 - Funding Information: The authors thank all patients and their families for participation in the trial. ModraDoc006 tablets were produced and provided by Modra Pharmaceuticals B.V. This study was financially supported by Modra Pharmaceuticals B.V. Publisher Copyright: © 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.

PY - 2021/8

Y1 - 2021/8

N2 - BACKGROUND: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).AIM: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.METHODS: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.RESULTS: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.CONCLUSION: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.

AB - BACKGROUND: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).AIM: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.METHODS: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.RESULTS: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.CONCLUSION: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.

KW - chemotherapy

KW - clinical trials

KW - drug discovery and delivery

KW - prostate cancer

UR - https://www.scopus.com/pages/publications/85102236806

U2 - 10.1002/cnr2.1367

DO - 10.1002/cnr2.1367

M3 - Article

C2 - 33709626

SN - 2573-8348

VL - 4

SP - 1

EP - 9

JO - Cancer reports (Hoboken, N.J.)

JF - Cancer reports (Hoboken, N.J.)

IS - 4

M1 - e1367

ER -

ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study

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