A Phase I Open-Label Dose Escalation Study of Intravenous INKmune In Patients With MDS or AML

Cancer Clinical Trial

— LAUREL  

Official title:

A Phase I Open-Label Dose Escalation Study Of Intravenous INKmune In Patients With Myelodysplastic Syndrome With Excess Blasts (MDS-EB-1/2 - MDS-CMML 1/2) Or Acute Myeloid Leukaemia (AML)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05933070
• Other study ID #: INMB-INB16-002
• Status: Terminated
• Phase: Phase 1
• Start date: June 15, 2020
• Est. completion date: April 26, 2024

Study information

• Verified date: April 2024
• Source: Inmune Bio, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

INMB-INB16-002 is a Phase I open-label, dose escalation study of INKmune therapy in subjects with myelodysplastic syndrome (MDS) with excess blasts without Auer rods (EB-1 or 2, or CMML 1 or 2) or subjects with acute myeloid leukaemia (AML) in complete remission.

Description:

INMB-INB16-002 is a Phase 1 open-label, dose escalation study of INKmune therapy in subjects with MDS with excess blasts without Auer rods (EB-1 or 2, or CMML 1 or 2) who have completed treatment with Azacytidine (AZA) and not achieved complete remission (CR) and who are not thought to be fit for intensive chemotherapy, or subjects with AML in complete remission (or complete remission with incomplete count recovery) unsuitable for intensive chemotherapy or allogeneic stem cell transplantation or subjects with relapsed MDS or AML post-allogeneic stem cell transplant with slowly progressive disease unsuitable for intensive chemotherapy.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: April 26, 2024
• Est. primary completion date: March 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject is = 18 years old.

2. Subjects with:

1. MDS-EB-1/2, MDS-CMML 1-2 who have completed treatment with Azacytidine (AZA), and not achieved complete remission (CR) who are not thought to be fit for intensive chemotherapy.

2. Subjects with AML in complete remission (or complete remission with incomplete count recovery) unsuitable for intensive chemotherapy or allogeneic stem cell transplantation.

3. Subjects with relapsed MDS or AML post-allogeneic stem cell transplant, with slowly progressive disease unsuitable for intensive chemotherapy.

3. Subject has adequate organ and marrow function (as defined below):

1. Serum creatinine = 1.5 X ULN, or measured creatinine clearance = 60 ml/min/1.73m2.

2. Aspartate aminotransferase (AST) and ALT levels = 3 X ULN.

3. Total bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert's syndrome.

4. Absolute neutrophil (ANC) = 500/mm3; 0.5 x 109/L

5. Platelet count = 50,000/mm3; 50 x 109/L

6. Haemoglobin = 100mg/L (transfusion to obtain haemoglobin = 100mg/L within 24 hours prior to dosing is allowed).

4. Subject must be at least 21 days from previous anticancer therapy (eg, chemotherapy, radiation therapy, immunotherapy and monoclonal antibodies, or investigational therapeutic agents) at the time of study screening and meet criteria in "3" above.

5. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status = 2.

6. a. Sexually active female subjects of childbearing potential must agree to use a highly effective method of contraception for the duration of study therapy and for 3 months after the last dose of INKmune. Acceptable forms of contraception methods are

as follows:

• Non-hormonal methods (i.e. intrauterine device, IUD)
• have vasectomised partner (the vasectomised partner must be the sole partner of the trial participant and have received medical assessment of its surgical success)
• True sexual abstinence Women of childbearing potential must discontinue any hormonal forms of birth control at least 4 weeks prior to first study dosing and commence using a highly effective, non- hormonal method as described above. Any pregnancy that occurs for study participants should be monitored for potential side effects. b. Male subjects with partners who are of childbearing potential must agree a double barrier method of contraception i.e. condom with either cap or diaphragm for the duration of study therapy and for 3 months after the last dose of INKmune. Male subjects with partners who are pregnant must use a condom for the same duration to avoid INKmune exposure to developing foetus. Note: Subjects who are abstinent (defined as refraining from heterosexual intercourse during the entire period of risk associated with study treatments), must agree to remain abstinent for the study duration and for 3 months after the last study dose of INKmune. The reliability of sexual abstinence will be evaluated in relation to the preferred and usual lifestyle of the subject.

7. Subject, must be able to understand and voluntarily sign a written informed consent, and are willing and able to comply with the protocol requirements.

8. Subject must have a life expectancy greater than 3 months in the opinion of the PI.

Exclusion Criteria:

1. Subject diagnosed with any other sub-classification of MDS.

2. Subject is currently receiving cancer-specific treatment with the exceptions of supportive treatments such as bisphosphonate or steroid treatments for symptomatic control.

3. Subject has had prior NK cell targeting therapy.

4. Subject has a current requirement for steroids > 10 mg daily; prednisolone or equivalent.

5. Subject has impaired cardiac function or clinically significant cardiac disease

including the following:

1. New York Heart Association grade III or IV congestive heart failure.

2. Myocardial infarction within the last 6 months prior to dosing with INKmune

3. Impaired left ventricular ejection fraction (LVEF < 40%) as assessed according to institutional standards.

6. Subject has shown lack of recovery of prior AEs to Grade =1 severity (NCI CTCAE v5.0) (except alopecia) due to therapy administered prior to the initiation of study drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as determined on a case-by-case basis at the discretion of the PI and Medical Monitor.

7. Subject has known allergy to any of the formulation components of INKmune.

8. Subjects has active, severe infection requiring systemic treatment. Subjects may become eligible once infection has resolved and they are at least seven days from completion of antibiotics.

9. Subject concomitant use of complementary or alternative medication or other agents (investigational therapeutic agents) will not be allowed without approval of a PI or sub- investigator (SI). Every effort will be made to maximize subject safety and minimize changes in chronic medications.

10. Subject is pregnant or is currently breastfeeding.

11. Subject has uncontrolled seizures as determined by the PI.

12. Subject has any other condition or finding that in the opinion of the PI or Sponsor Medical Monitor may render the subject at excessive risk for treatment complications or may not be able provide evaluable outcome information.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• AML
• Cancer
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• MDS-EB
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Biological:
• INKmune
INKmune is a patented biologic delivery system and method for cancer treatment using in vivo priming and activation of natural killer (NK) cells in order to achieve tumor cell lysis. INKmune is a suspension of INB16 cells which have been rendered replication incompetent. INKumne is a replication-incompetent tumor cell line that does not require donor matching.

Locations

Country	Name	City	State
Greece	Attikon University General Hospital	Athens	Attiki
United Kingdom	Sheffield Teaching Hospitals NHS FT - Royal Hallamshire Hospital	Sheffield
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton	Hampshire

Sponsors (1)

Lead Sponsor	Collaborator
Inmune Bio, Inc.

Countries where clinical trial is conducted

Greece,  United Kingdom, 

References & Publications (26)

Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy. 2008;10(6):625-32. doi: 10.1080/14653240802301872. — View Citation

Bengala, C., V. Rasini, R. Sternieri, M. Dominici, A. Andreotti, R. Gelmini, L. Cafarelli, P. Bevini, A. Berti, and P. Conte. 2007. 'Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis', Journal of Clinical Oncology, 25: 3054-54.

Bryceson YT, March ME, Ljunggren HG, Long EO. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev. 2006 Dec;214:73-91. doi: 10.1111/j.1600-065X.2006.00457.x. — View Citation

Carlsten M, Baumann BC, Simonsson M, Jadersten M, Forsblom AM, Hammarstedt C, Bryceson YT, Ljunggren HG, Hellstrom-Lindberg E, Malmberg KJ. Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia. 2010 Sep;24(9):1607-16. doi: 10.1038/leu.2010.149. Epub 2010 Jul 8. — View Citation

Carlsten M, Norell H, Bryceson YT, Poschke I, Schedvins K, Ljunggren HG, Kiessling R, Malmberg KJ. Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J Immunol. 2009 Oct 15;183(8):4921-30. doi: 10.4049/jimmunol.0901226. — View Citation

Cesano A, Santoli D. Two unique human leukemic T-cell lines endowed with a stable cytotoxic function and a different spectrum of target reactivity analysis and modulation of their lytic mechanisms. In Vitro Cell Dev Biol. 1992 Sep-Oct;28A(9-10):648-56. doi: 10.1007/BF02631041. — View Citation

Chandhok NS, Boddu PC, Gore SD, Prebet T. What are the most promising new agents in myelodysplastic syndromes? Curr Opin Hematol. 2019 Mar;26(2):77-87. doi: 10.1097/MOH.0000000000000483. — View Citation

Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, Zou J, Ku E, Zhong B, Boulware D, Moscinski L, Wei S, Djeu JY, List AF. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007 Jun 1;109(11):4816-24. doi: 10.1182/blood-2006-07-035519. Epub 2007 Mar 6. — View Citation

Fehniger TA, Miller JS, Stuart RK, Cooley S, Salhotra A, Curtsinger J, Westervelt P, DiPersio JF, Hillman TM, Silver N, Szarek M, Gorelik L, Lowdell MW, Rowinsky E. A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia. Biol Blood Marrow Transplant. 2018 Aug;24(8):1581-1589. doi: 10.1016/j.bbmt.2018.03.019. Epub 2018 Mar 27. — View Citation

Fozza C. The burden of autoimmunity in myelodysplastic syndromes. Hematol Oncol. 2018 Feb;36(1):15-23. doi: 10.1002/hon.2423. Epub 2017 Apr 27. — View Citation

Gong JH, Maki G, Klingemann HG. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia. 1994 Apr;8(4):652-8. — View Citation

Hou HA, Tsai CH, Lin CC, Chou WC, Kuo YY, Liu CY, Tseng MH, Peng YL, Liu MC, Liu CW, Liao XW, Lin LI, Yao M, Tang JL, Tien HF. Incorporation of mutations in five genes in the revised International Prognostic Scoring System can improve risk stratification in the patients with myelodysplastic syndrome. Blood Cancer J. 2018 Apr 4;8(4):39. doi: 10.1038/s41408-018-0074-7. — View Citation

Kiladjian JJ, Bourgeois E, Lobe I, Braun T, Visentin G, Bourhis JH, Fenaux P, Chouaib S, Caignard A. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia. 2006 Mar;20(3):463-70. doi: 10.1038/sj.leu.2404080. — View Citation

Kottaridis PD, North J, Tsirogianni M, Marden C, Samuel ER, Jide-Banwo S, Grace S, Lowdell MW. Two-Stage Priming of Allogeneic Natural Killer Cells for the Treatment of Patients with Acute Myeloid Leukemia: A Phase I Trial. PLoS One. 2015 Jun 10;10(6):e0123416. doi: 10.1371/journal.pone.0123416. eCollection 2015. — View Citation

Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008 May;9(5):495-502. doi: 10.1038/ni1581. — View Citation

Loghavi S, Sui D, Wei P, Garcia-Manero G, Pierce S, Routbort MJ, Jabbour EJ, Pemmaraju N, Kanagal-Shamanna R, Gur HD, Hu S, Zuo Z, Medeiros LJ, Kantarjian HM, Khoury JD. Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories. Blood Adv. 2018 Aug 14;2(15):1807-1816. doi: 10.1182/bloodadvances.2018019224. — View Citation

Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity. 2007 Apr;26(4):503-17. doi: 10.1016/j.immuni.2007.03.006. Epub 2007 Mar 29. — View Citation

Nazha A, Bejar R. Molecular Data and the IPSS-R: How Mutational Burden Can Affect Prognostication in MDS. Curr Hematol Malig Rep. 2017 Oct;12(5):461-467. doi: 10.1007/s11899-017-0407-9. — View Citation

North J, Bakhsh I, Marden C, Pittman H, Addison E, Navarrete C, Anderson R, Lowdell MW. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. J Immunol. 2007 Jan 1;178(1):85-94. doi: 10.4049/jimmunol.178.1.85. — View Citation

Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013 Nov 21;122(22):3616-27; quiz 3699. doi: 10.1182/blood-2013-08-518886. Epub 2013 Sep 12. — View Citation

Sabry M, Lowdell MW. Tumor-primed NK cells: waiting for the green light. Front Immunol. 2013 Nov 25;4:408. doi: 10.3389/fimmu.2013.00408. — View Citation

Sabry M, Zubiak A, Hood SP, Simmonds P, Arellano-Ballestero H, Cournoyer E, Mashar M, Pockley AG, Lowdell MW. Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. PLoS One. 2019 Jun 26;14(6):e0218674. doi: 10.1371/journal.pone.0218674. eCollection 2019. — View Citation

Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, Suttorp M, Seifried E, Ottmann OG, Bug G. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy. 2013 Dec;15(12):1563-70. doi: 10.1016/j.jcyt.2013.06.017. Epub 2013 Oct 1. — View Citation

Tsirogianni M, Grigoriou E, Kapsimalli V, Dagla K, Stamouli M, Gkirkas K, Konsta E, Karagiannidou A, Gkodopoulos K, Stavroulaki G, Pappa V, Angelopoulou M, Lowdell M, Tsirigotis P. Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine. Leuk Lymphoma. 2019 Oct;60(10):2457-2463. doi: 10.1080/10428194.2019.1581935. Epub 2019 Apr 5. — View Citation

Visonneau S, Cesano A, Porter DL, Luger SL, Schuchter L, Kamoun M, Torosian MH, Duffy K, Sickles C, Stadtmauer EA, Santoli D. Phase I trial of TALL-104 cells in patients with refractory metastatic breast cancer. Clin Cancer Res. 2000 May;6(5):1744-54. — View Citation

Williams BA, Law AD, Routy B, denHollander N, Gupta V, Wang XH, Chaboureau A, Viswanathan S, Keating A. A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy. Oncotarget. 2017 Jul 12;8(51):89256-89268. doi: 10.18632/oncotarget.19204. eCollection 2017 Oct 24. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Objective 1	Assess the pharmacodynamics (PD) (proof of biology) of INKmune by analyzing NK cells obtained from peripheral blood, and bone marrow as available and to measure primed NK cells and cell kill ability using the tumour killing assay.	2-3 years
Primary	Primary Objective 1	Identify the incidence and seriousness of AEs and their relationship (causality) to INKmune as graded by NCI CTCAE criteria v.5.0.	2-3 years
Primary	Primary Objective 2	Identify a RP2D of INKmune. The RP2D is defined as the maximum tolerated dose (MTD) of the agent which will be defined as the dose at which the complication rate is less than 33%.	2-3 years
Secondary	Secondary Objective 1	To assess the overall response rate by measuring changes in percentage blasts in PB at days 29, 43, 73, 119 and BM at day 29.	1-2 years
Secondary	Secondary Objective 2	To assess the overall response rate, partial response rate or complete response rate in subjects administered INKmune using the WHO criteria by measuring changes in vital signs, electrocardiogram (ECG), and safety laboratory parameters throughout the study.	3-4 years
Secondary	Secondary Objective 3	To assess the progression-free survival (PFS) time defined as time to increase in transfusion dependence and or increase in percentage blasts in Peripheral Blood (PB) and/or Bone Marrow (BM).	2-3 years