PD-1 Knockout Engineered T Cells for Metastatic Renal Cell Carcinoma.

NCT02867332 | Withdrawn Phase 1 DMC

• 1 other identifier: 11007965940
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic advanced renal cancer. Blood samples will also be collected for research purposes.

Conditions

Metastatic Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and tolerability of dose of PD-1 Knockout T cells using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients

  Dose Escalation - Approximately 6 months

Secondary Outcomes (7)

• Response Rate:Response will be evaluated according to RECIST v1.1

  90 days

• Progression free survival - PFS

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to average 10 months

• Overall Survival - OS

  The time from randomization to death from any cause, assessed up to 2 years

• Peripheral blood circulating tumor DNA

  6 weeks

• Temporal Interleukin-2 change in the peripheral blood

  Baseline and 1 month and 3 months

Study Arms (2)

Test group

EXPERIMENTAL

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10\^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third.Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/ day (if tolerant). Patients will receive a total of 2, 3, 4 cycles of treatment.

Biological: PD-1 Knockout T Cells; Drug: Cyclophosphamide; Drug: IL-2

Comparable group

PLACEBO COMPARATOR

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will not be knocked out by CRISPR Cas9 in the laboratory (PD-1 Wild-type T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10\^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third.Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/ day (if tolerant). Patients will receive a total of 2, 3, 4 cycles of treatment.

Drug: Cyclophosphamide; Drug: IL-2

Interventions

PD-1 Knockout T Cells BIOLOGICAL

PD-1 Knockout T Cells and PD-1 wild-type T Cells will be made by Cell Biotech Co., Ltd. 2x107/kg T cells will be used for test group and comparable group separately.

Test group

Cyclophosphamide DRUG

Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/day (if tolerant).

Also known as: cytophosphane

Comparable group; Test group

IL-2 DRUG

Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/ day (if tolerant).

Also known as: Interleukin-2 (IL-2)

Comparable group; Test group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologically verified stage IV Renal cancer with measurable lesions (On CT: longest diameter of tumoral lesion \>=10 mm, shorted diameter of lymph node \>=15 mm; measurable lesions should not have been irradiated)
• Progressed after all standard treatment
• Performance score: 0-1
• Expected life span: \>= 6 months
• Toxicities from prior treatment has resolved. Washout period is 4 weeks for chemotherapy, and 2 weeks for targeted therapy
• Major organs function normally
• Women at pregnant ages should be under contraception
• Willing and able to provide informed consent

You may not qualify if:

• Pathology is mixed type
• Emergent treatment of tumor emergency is needed
• Poor vasculature
• Coagulopathy, or ongoing thrombolytics and/or anticoagulation
• Blood-borne infectious disease, e.g. hepatitis B
• History of mandatory custody because of psychosis or other psychological disease inappropriate for treatment deemed by treating physician
• With other immune diseases, or chronic use of immunosuppressants or steroids
• Compliance cannot be expected

Sponsors & Collaborators

• Peking University: lead

Related Publications (6)

• Gandini S, Massi D, Mandala M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016 Apr;100:88-98. doi: 10.1016/j.critrevonc.2016.02.001. Epub 2016 Feb 10.

  PMID: 26895815 BACKGROUND

• Koshkin VS, Rini BI. Emerging therapeutics in refractory renal cell carcinoma. Expert Opin Pharmacother. 2016 Jun;17(9):1225-32. doi: 10.1080/14656566.2016.1182987. Epub 2016 May 23.

  PMID: 27112171 RESULT

• Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Goppner D, Hassel JC, Meier F, Tietze JK, Thomas I, Weishaupt C, Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016 Jun;60:190-209. doi: 10.1016/j.ejca.2016.02.025. Epub 2016 Apr 13.

  PMID: 27085692 RESULT

• Gunturi A, McDermott DF. Potential of new therapies like anti-PD1 in kidney cancer. Curr Treat Options Oncol. 2014 Mar;15(1):137-46. doi: 10.1007/s11864-013-0268-y.

  PMID: 24504486 RESULT

• Bockorny B, Dasanu CA. Intrinsic immune alterations in renal cell carcinoma and emerging immunotherapeutic approaches. Expert Opin Biol Ther. 2013 Jun;13(6):911-25. doi: 10.1517/14712598.2013.778970. Epub 2013 Apr 16.

  PMID: 23586712 RESULT

• Yi L, Li J. CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges. Biochim Biophys Acta. 2016 Dec;1866(2):197-207. doi: 10.1016/j.bbcan.2016.09.002. Epub 2016 Sep 15.

  PMID: 27641687 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Cyclophosphamide; Interleukin-2

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 11, 2016
• First Posted: August 15, 2016
• Study Start: November 1, 2016
• Primary Completion: November 1, 2020
• Study Completion: November 1, 2020
• Last Updated: March 6, 2019

Record last verified: 2016-08